Impact of achieving a complete response to initial therapy of multiple myeloma and predictors of subsequent outcome

Abstract Maintenance therapy has become a hot field in myeloma, and it may be particularly relevant in elderly patients because the major benefit results from the initial therapy. We report the results of a randomized comparison of maintenance with bortezomib plus thalidomide (VT) or prednisone (VP) in 178 elderly untreated myeloma patients who had received 6 induction cycles with bortezomib plus either melphalan and prednisone or thalidomide and prednisone. The complete response (CR) rate increased from 24% after induction up to 42%, higher for VT versus VP (46% vs 39%). Median progression-free survival (PFS) was superior for VT (39 months) compared with VP (32 months) and overall survival (OS) was also longer in VT patients compared with VP (5-year OS of 69% and 50%, respectively) but the differences did not reach statistical significance. CR achievement was associated with a significantly longer PFS (P < .001) and 5-year OS (P < .001). The incidence of G3-4 peripheral neuropathy was 9% for VT and 3% for VP. Unfortunately, this approach was not able to overcome the adverse prognosis of cytogenetic abnormalities. In summary, these maintenance regimens result in a significant increase in CR rate, remarkably long PFS, and acceptable toxicity profile. The trial is registered at www.clinicaltrials.gov as NCT00443235.

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Pericardial relapse of multiple myeloma

BMJ Case Reports ◽

10.1136/bcr-2019-233340 ◽

2020 ◽

Vol 13 (4) ◽

pp. e233340

Author(s):

Lee S Jamison ◽

Clifton Craig Mo ◽

Mary Kwok

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Poor Prognosis ◽

Stem Cell Transplant ◽

Complete Response ◽

Initial Therapy ◽

Autologous Stem Cell Transplant ◽

Cell Transplant ◽

Extramedullary Relapse ◽

To Receive

In patients who experience relapse of multiple myeloma, upwards of 30% can have extramedullary disease. The presence of extramedullary multiple myeloma is typically associated with adverse cytogenetics and a poor prognosis. Organs most commonly involved include the liver, skin, central nervous system, pleural effusions, kidney, lymph nodes, and pancreas. We present the case of a 53-year-old man with IgA kappa multiple myeloma with the adverse cytogenetic findings of t(4;14) and 1q21 gain who had achieved a stringent complete (sCR) response after initial therapy with carfilzomib, lenalidomide and dexamethasone. Stringent complete response is defined as the normalization of the free light chain ratio in the serum and an absence of clonal cells in the bone marrow in additiion to criteria needed to achieve complete response. Prior to undergoing a planned autologous stem cell transplant, this patient experienced cardiac tamponade secondary to extramedullary relapse of his multiple myeloma which was limited to the pericardium. In response, his treatment regimen was transitioned to pomalidomide, bortezomib, dexamethasone and cyclophosphamide for three cycles after which he again achieved sCR and ultimately underwent autologous stem cell transplant. Post-transplant consolidation therapy was administered in the form of pomalidomide, bortezomib and dexamethasone, followed by pomalidomide and bortezomib maintenance, which he has continued to receive for 3 years without evidence of disease progression.

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Autologous Transplantation, Consolidation, and Maintenance Therapy in Multiple Myeloma: Results of the BMT CTN 0702 Trial

Journal of Clinical Oncology ◽

10.1200/jco.18.00685 ◽

2019 ◽

Vol 37 (7) ◽

pp. 589-597 ◽

Cited By ~ 63

Author(s):

Edward A. Stadtmauer ◽

Marcelo C. Pasquini ◽

Beth Blackwell ◽

Parameswaran Hari ◽

Asad Bashey ◽

...

Keyword(s):

Multiple Myeloma ◽

Hematopoietic Cell Transplantation ◽

Autologous Transplantation ◽

Progression Free Survival ◽

Complete Response ◽

Drug Regimen ◽

Initial Therapy ◽

Phase Iii ◽

Second Primary ◽

Second Primary Malignancies

PURPOSE Single-cycle melphalan 200 mg/m2 and autologous hematopoietic cell transplantation (AHCT) followed by lenalidomide (len) maintenance have improved progression-free survival (PFS) and overall survival (OS) for transplantation-eligible patients with multiple myeloma (MM). We designed a prospective, randomized, phase III study to test additional interventions to improve PFS by comparing AHCT, tandem AHCT (AHCT/AHCT), and AHCT and four subsequent cycles of len, bortezomib, and dexamethasone (RVD; AHCT + RVD), all followed by len until disease progression. PATIENTS AND METHODS Patients with symptomatic MM within 12 months from starting therapy and without progression who were age 70 years or younger were randomly assigned to AHCT/AHCT + len (n = 247), AHCT + RVD + len (n = 254), or AHCT + len (n = 257). The primary end point was 38-month PFS. RESULTS The study population had a median age of 56 years (range, 20 to 70 years); 24% of patients had high-risk MM, 73% had a triple-drug regimen as initial therapy, and 18% were in complete response at enrollment. The 38-month PFS rate was 58.5% (95% CI, 51.7% to 64.6%) for AHCT/AHCT + len, 57.8% (95% CI, 51.4% to 63.7%) for AHCT + RVD + len, and 53.9% (95% CI, 47.4% to 60%) for AHCT + len. For AHCT/AHCT + len, AHCT + RVD + len, and AHCT + len, the OS rates were 81.8% (95% CI, 76.2% to 86.2%), 85.4% (95% CI, 80.4% to 89.3%), and 83.7% (95% CI, 78.4% to 87.8%), respectively, and the complete response rates at 1 year were 50.5% (n = 192), 58.4% (n = 209), and 47.1% (n = 208), respectively. Toxicity profiles and development of second primary malignancies were similar across treatment arms. CONCLUSION Second AHCT or RVD consolidation as post-AHCT interventions for the up-front treatment of transplantation-eligible patients with MM did not improve PFS or OS. Single AHCT and len should remain as the standard approach for this population.

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Initial Therapy of Multiple Myeloma Patients Who Are Not Candidates for Stem Cell Transplantation

Hematology ◽

10.1182/asheducation-2006.1.338 ◽

2006 ◽

Vol 2006 (1) ◽

pp. 338-347 ◽

Cited By ~ 7

Author(s):

Robert Z. Orlowski

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Proteasome Inhibitors ◽

Standard Of Care ◽

Complete Response ◽

Drug Regimen ◽

Initial Therapy ◽

Phase Iii ◽

High Dose ◽

Phase Ii Studies

Abstract Multiple myeloma patients deemed to not be candidates for high-dose therapy followed by stem cell rescue who nonetheless need chemotherapy have traditionally received an oral regimen combining melphalan and prednisone. With the advent of novel agents, however, such as immunomodulatory drugs and proteasome inhibitors that are active in the relapsed/refractory setting, there has been an impetus to incorporate these new options into front-line therapy. Several phase II studies have recently revealed that addition of either thalidomide, lenalidomide, or bortezomib to melphalan and prednisone increased the overall and complete response rates, albeit at the cost of some increased toxicity. Randomized phase III studies of melphalan and prednisone with thalidomide have already shown that, compared to melphalan and prednisone alone, the three-drug regimen prolonged time to progression and overall survival in this population, thereby defining a new standard of care. Moreover, our increasing knowledge of the molecular role that cytogenetic abnormalities play in the biology of multiple myeloma and our growing chemotherapeutic armamentarium are beginning to allow us to rationally select therapies based on these characteristics of each patient’s disease. Such a risk- and molecular-adapted strategy to the therapy of multiple myeloma promises to revolutionize and personalize our care of these patients and bring us closer to a cure for this disease.

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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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MASS-FIX versus standard methods to predict for PFS and OS among multiple myeloma patients participating on the STAMINA trial.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.8009 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 8009-8009

Author(s):

Angela Dispenzieri ◽

Amrita Y. Krishnan ◽

Bonnie Arendt ◽

Surendra Dasari ◽

Yvonne Adeduni Efebera ◽

...

Keyword(s):

Mass Spectrometry ◽

Multiple Myeloma ◽

Flow Cytometry ◽

Multiple Testing ◽

Residual Disease ◽

Progression Free Survival ◽

Complete Response ◽

Independent Effect ◽

Next Generation ◽

Different Response

8009 Background: Measuring response among patients with multiple myeloma is essential for the care of patients. Deeper responses have been associated with better progression free survival (PFS) and overall survival (OS). Serum (SIFE) and urine immunofixation are the currently used markers for biochemical documentation of CR after which marrow is tested for plasma cell clearance. Next generation flow cytometry and sequencing are used to document the presence of minimal residual disease (MRD). Mass spectrometry of blood by MALDI (Mass-Fix) is a new simple, inexpensive, sensitive, and specific means of detecting monoclonal immunoglobulins. To better test the hypothesis that Mass-Fix is superior to existing methodologies to predict for survival outcomes—especially SIFE-- samples from the STAMINA trial (NCT01109004), a trial comparing 3 transplant approaches among patients who have already received induction, were employed. Methods: Five-hundred and seventy-five patients were included. Samples from enrollment post-induction (post-I) and 1-year post enrollment (1YR) were tested when available. Four response parameters were assessed univariately: Mass-Fix, SIFE, complete response, and MRD by next generation flow cytometry. Mass spectrometry spectra were evaluated in a blinded fashion. Complete response was according to the 2006 International Myeloma Working Group criteria. Multivariate Cox proportional hazard models using stepwise regression were developed to explore the independent effect of the different response parameters on PFS and OS and interactions with other risk factors. Results: Of the 4 response measures, only MRD and Mass-Fix predicted for PFS and OS at multiple testing points on multivariate analyses (Table). Of the 4 post-I measurements, only MRD predicted for PFS; however, Mass-Fix was the only post-I measurement to predict for OS. Of all the 1-year measures, both 1YR Mass-Fix and 1YR MRD positivity predicted for inferior PFS and OS. In models including MRD and Mass-Fix, SIFE and CR were not prognostic for PFS or OS. Conclusions: Mass-Fix is a powerful means to track monoclonal proteins. The full utility of Mass-Fix was not exploited given the absence of a diagnostic sample and the fact that only serum (and not urine) was tested. Despite these limitations, it performed well at pre-induction and at 1 year. Mass-Fix provides a convenient and non-invasive means of predicting for myeloma outcomes. Clinical trial information: NCT01109004. [Table: see text]

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Consolidation and Maintenance in Newly Diagnosed Multiple Myeloma

Journal of Clinical Oncology ◽

10.1200/jco.21.01045 ◽

2021 ◽

pp. JCO.21.01045

Author(s):

Pieter Sonneveld ◽

Meletios A. Dimopoulos ◽

Meral Beksac ◽

Bronno van der Holt ◽

Sara Aquino ◽

...

Keyword(s):

Multiple Myeloma ◽

Minimal Residual Disease ◽

Residual Disease ◽

Progression Free Survival ◽

Complete Response ◽

Primary Study ◽

Controlled Clinical Trial ◽

Newly Diagnosed ◽

Consolidation Treatment ◽

Minimal Residual

PURPOSE To address the role of consolidation treatment for newly diagnosed, transplant eligible patients with multiple myeloma in a controlled clinical trial. PATIENTS AND METHODS The EMN02/HOVON95 trial compared consolidation treatment with two cycles of bortezomib, lenalidomide, and dexamethasone (VRD) or no consolidation after induction and intensification therapy, followed by continuous lenalidomide maintenance. Primary study end point was progression-free survival (PFS). RESULTS Eight hundred seventy-eight eligible patients were randomly assigned to receive VRD consolidation (451 patients) or no consolidation (427 patients). At a median follow-up of 74.8 months, median PFS with adjustment for pretreatment was prolonged in patients randomly assigned to VRD consolidation (59.3 v 42.9 months, hazard ratio [HR] = 0.81; 95% CI, 0.68 to 0.96; P = .016). The PFS benefit was observed across most predefined subgroups, including revised International Staging System (ISS) stage, cytogenetics, and prior treatment. Revised ISS3 stage (HR, 2.00; 95% CI, 1.41 to 2.86) and ampl1q (HR, 1.67; 95% CI, 1.37 to 2.04) were significant adverse prognostic factors. The median duration of maintenance was 33 months (interquartile range 13-86 months). Response ≥ complete response (CR) after consolidation versus no consolidation before start of maintenance was 34% versus 18%, respectively ( P < .001). Response ≥ CR on protocol including maintenance was 59% with consolidation and 46% without ( P < .001). Minimal residual disease analysis by flow cytometry in a subgroup of 226 patients with CR or stringent complete response or very good partial response before start of maintenance demonstrated a 74% minimal residual disease–negativity rate in VRD-treated patients. Toxicity from VRD was acceptable and manageable. CONCLUSION Consolidation treatment with VRD followed by lenalidomide maintenance improves PFS and depth of response in newly diagnosed patients with multiple myeloma as compared to maintenance alone.

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Lenalidomide for Initial Therapy of Newly Diagnosed Multiple Myeloma

Myeloma Therapy ◽

10.1007/978-1-59745-564-0_18 ◽

2008 ◽

pp. 279-288

Author(s):

Shaji Kumar

Keyword(s):

Multiple Myeloma ◽

Initial Therapy ◽

Newly Diagnosed

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Efficacy and safety of daratumumab in the treatment of multiple myeloma: a systematic review and meta-analysis

Journal of International Medical Research ◽

10.1177/03000605211038135 ◽

2021 ◽

Vol 49 (8) ◽

pp. 030006052110381

Author(s):

Yin Wang ◽

Yanqing Li ◽

Ye Chai

Keyword(s):

Multiple Myeloma ◽

Meta Analysis ◽

Complete Response ◽

Library Science ◽

Cochrane Library ◽

Control Group ◽

Efficacy And Safety ◽

Risk Patients ◽

Grade 3 ◽

Combination Regimens

Objective To systematically evaluate the efficacy and safety of combination regimens containing daratumumab in patients with multiple myeloma (MM). Methods A systematic search of publications listed on electronic databases (PubMed®, The Cochrane Library, Science Direct and Web of Science) between inception and 13 November 2020 was conducted to find randomized controlled trials (RCTs) that included patients with MM that were treated with combination regimens containing daratumumab. Results A total of seven RCTs were included ( n = 4268 patients). Meta-analysis showed that compared with the control group, the group containing daratumumab showed a significantly better overall response rate and a complete response or better. Daratumumab improved efficacy in both standard-risk and cytogenetically high-risk patients with MM. The prevalence of neutropenia (≥grade 3) and pneumonia was significantly higher in the daratumumab group compared with the control group. Conclusion The available evidence demonstrated that the clinical application of combination regimens containing daratumumab improved the efficacy in patients with MM and had acceptable safety.

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Autologous haematopoietic stem cell transplantation in patients with multiple myeloma complicated by dialysis-dependent renal failure

Terapevticheskii arkhiv ◽

10.26442/00403660.2020.07.000777 ◽

2020 ◽

Vol 92 (7) ◽

pp. 70-76

Author(s):

M. V. Firsova ◽

L. P. Mendeleeva ◽

M. V. Solovev ◽

I. G. Rekhtina ◽

O. S. Pokrovskaya ◽

...

Keyword(s):

Multiple Myeloma ◽

Renal Failure ◽

Stem Cell ◽

Partial Response ◽

Stem Cell Transplantation ◽

Haematopoietic Stem Cell Transplantation ◽

Complete Response ◽

Haematopoietic Stem Cell ◽

Renal Response ◽

Good Partial Response

Aim.To assess the safety and efficacy of autologous haematopoietic stem cell transplantation (auto-HSCT) in multiple myeloma (MM) patients with dialysis-dependent renal failure. Materials and methods.During a period from May 2010 to December 2016 fourteen MM patients with dialysis-dependent renal failure aged 48 to 65 years underwent auto-HSCT. After the induction therapy complete response, very good partial response, partial response were documented in 64, 29, 7% of patients, respectively. In no case was a renal response achieved. Haematopoietic stem cell mobilization in most patients (13/14) was performed according to the scheme: G-CSF 10 g/kg. Melphalan in 3 dosages was used as pre-transplant conditioning: 100, 140 and 200 mg/m2; 13 patients underwent a single and in one case underwent a tandem auto-HSCT against the background of hemodialysis. Evaluation of the antitumor and renal response was assessed on the 100th day after auto-HSCT. Subsequently, against the background of programmed hemodialysis and in the setting of high-dosed melphalan (100200 mg/m2), 13 patients underwent a single and one patient underwent a tandem auto-HSCT. At +100 days after auto-HSCT, an antitumor response and renal response were assessed. Results.The period of agranulocytosis after auto-HSCT was from 5 to 12 days (median 8,5) and was accompanied by infectious complications, cardiac and neurological dysfunctions. At +100 days after auto-HSCT, the complete response was confirmed in 71% patients and very good partial response was confirmed in 29% patients. The minimal renal response was registered in 2 patients (14%), hemodialysis was stopped. The transplant-related mortality was absent. After a median follow-up of 53 months 5-year progression-free survival was 59%, and overall survival was 93%. Conclusion.Carrying out auto-HSCT in patients with dialysis-dependent renal failure contributed to the achievement of a minimal renal response in 14% of cases, which allowed these patients to stop hemodialysis. Patients whose conditioning regimen was performed using melphalan at a dose of 200 mg/m2showed more frequent complications in the early post-transplant period compared to patients who received a lower dose of melphalan (100140 mg/m2). Auto-HSCT in MM patients with dialysis-dependent renal failure is a feasible and effective treatment method, which in some cases contributes to independence from hemodialysis.

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