Proliferation to Apoptosis Tumor Cell Ratio as a Biomarker to Improve Clinical Management of Pre-Malignant and Symptomatic Plasma Cell Neoplasms

Proliferation and apoptosis of neoplastic cells are prognostic biomarkers in plasma cell neoplasms (PCNs). The prognostic capacity of proliferation to apoptosis ratio (Ratio-PA) in the era of immunomodulatory treatments is re-evaluated in 316 gammopathy of undetermined significance (MGUS), 57 smoldering multiple myeloma (SMM), and 266 multiple myeloma (MM) patients. Ratio-PA of 0.77 ± 0.12, 1.94 ± 0.52, and 11.2 ± 0.7 (p < 0.0001) were observed in MGUS, SMM, and MM patients. Ten-year overall survival (10y-OS) rates for patients with low/high Ratio-PA were 93.5%/77.3% p < 0.0001) for MGUS, 82.5%/64.7% (p < 0.05) for SMM, and 62.3%/47.0% (p < 0.05) for MM. For patients with low, intermediate, and high risk, 10y-OS for low/high Ratio-PA were 95.5%/72.9% (p < 0.0001), 74.2%/50.4% (p < 0.0001), and 35.3%/20.0% (p = 0.836), respectively. Ratio-PA was an independent prognostic factor for OS (HR = 2.119, p < 0.0001, Harrell-C-statistic = 0.7440 ± 0.0194) when co-analyzed with sex, age, and standard risk. In patients with Ratio-PAhigh, only first-line therapy with VRd/VTd, but not PAD/VCD, coupled with ASCT was associated with high 10y-OS (82.7%). Tumor cell Ratio-PA estimated at diagnosis offers a prognostic biomarker that complements standard risk stratification and helps to guide the clinical management of pre-malignant and symptomatic PCNs. Every effort should be made to provide first-line therapies including VTd or VRd associated with ASCT to patients with Ratio-PAhigh at higher risk of progression and death.

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A Pilot Study of Lenalidomide and Dexamethasone as First Line Therapy in Patients with Primary Plasma Cell Leukemia.

Blood ◽

10.1182/blood.v114.22.4951.4951 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4951-4951

Author(s):

Pellegrino Musto ◽

Maria Teresa Petrucci ◽

Fortunato Morabito ◽

Francesco Nobile ◽

Fiorella D'Auria ◽

...

Keyword(s):

Multiple Myeloma ◽

Plasma Cell ◽

Plasma Cells ◽

Early Response ◽

Plasma Cell Leukemia ◽

Cell Leukemia ◽

First Line ◽

First Line Therapy ◽

Line Therapy ◽

Primary Plasma Cell Leukemia

Abstract Abstract 4951 Background Primary Plasma Cell Leukemia (PPCL) is an aggressive, rare variant of multiple myeloma, with clinical, molecular and phenotypic peculiarities, which accounts approximately for 2% to 4% of all myeloma diagnoses. The prognosis of PPCL patients is usually poor, with less than half of patients responding to conventional chemotherapy and a median survival of 7 months. Even by using autologous or allogeneic transplant procedures, survival generally does not exceed three years. Bortezomib has recently provided some promising results in this setting, but, given all the above, new treatments for PPCL are greatly awaited. Lenalidomide is a new immunomodulating agent with great efficacy in multiple myeloma, especially when associated with dexamethasone or other drugs. There are, indeed, some sporadic case reports of PPCL patients treated with lenalidomide as salvage therapy, but no data are currently available on the use of this drug as first line therapy in this disease. Patients and Methods On March, 2009, we started an open label, prospective, multicenter, exploratory, single arm, two-stage study aiming to evaluate safety and antitumor activity of the lenalidomide/low dose dexamethasone combination (Rd), as first line therapy in patients with PPCL. The primary endpoint was early response rate according to International Uniform Criteria. The secondary endpoints were TTP, PFS, OS, percentage of eligible PPCL patients able to collect peripheral blood stem cells and to undergo autologous or allogeneic stem cells transplantation after Rd, serious and severe adverse event rate. According to this study protocol, all eligible, newly diagnosed adult patients with PPCL receive Lenalidomide at a dose of 25 mg daily for 21 days every 28 days. Oral dexamethasone is administered at a dose of 40 mg daily on days 1, 8, 15, and 22 for each 28-day cycle. After 4 cycles, patients who achieve at least PR and not eligible for autologous or allogeneic stem cell transplantation, continue with Rd until clinically appropriate (disease progression, unacceptable toxicity, patient's decision to leave the protocol). In these patients, a maintenance dose of lenalidomide alone equal to 10 mg/die days 1-21 every month is considered after at least 8 full dose Rd cycles. Patients responding after 4 Rd cycles and eligible for transplant procedures, proceed according to single Centre transplant policy. Patients not responding after 4 cycles or progressing under Rd treatment are considered off-study. Appropriate contraception methods and anti-thrombotic prophylaxis are planned. Results Four enrolled patients (1 male, 3 female, mean age 65 years, range 58-69) are currently evaluable for early response. All had unfavourable cytogenetics, including del13, t(4;14), t (14;16), or a complex karyotype. Circulating plasma cells ranged from 4.4 to 9.2 ×10e9/l. One patient had at baseline a moderate degree of renal failure (serum creatinine levels 2 mg/dl). After at least 2 Rd cycles (range 2-4), two PR and two VGPR were achieved (overall response rate 100%), with disappearance or near complete reduction of circulating plasma cells in all cases. The most relevant toxicities were grade 3 neutropenia and pneumonia, occurring in one patient and resolved by appropriate lenalidomide dose reduction, introduction of G-CSF and antibiotic therapy. One patient died in PR, due to causes unrelated to PPCL or treatment. As, according to the Simon, two-stage design adopted, more than two responses occurred within the first ten patients enrolled (stage 1), a total of 22 PPCL subjects will be accrued to complete the stage 2 of the trial. Conclusions These findings, though very preliminary, suggest that the combination of lenalidomide and dexamethasone may be a safe and promising initial therapy for PPCL patients, which can rapidly control the disease and could permit to perform following single patient-adapted therapeutic strategies. An update of this study, including molecular data, a larger number of patients and a longer follow-up, will be presented at the Meeting. Disclosures Musto: Janssen-Cilag: Honoraria; Celgene: Honoraria, Research Funding. Off Label Use: Lenalidomide is approved in Italy for advanced multiple myeloma, not for plasma cell leukemia. This is a clinical trial registered at AIFA (Italian regulatory Agency for Drugs), EudraCT No. 2008-003246 28. Petrucci:Janssen-Cilag: Honoraria; Celgene: Honoraria. Morabito:Celgene: Honoraria; Janssen-Cilag: Honoraria. Cavo:Celgene: Honoraria; Janssen-Cilag: Honoraria. Boccadoro:Celgene: Honoraria; Janssen-Cilag: Honoraria. Palumbo:Celgene: Honoraria; Janssen-Cilag: Honoraria.

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Bortezomib in first-line therapy is associated with falls in older adults with multiple myeloma

Journal of Geriatric Oncology ◽

10.1016/j.jgo.2021.02.009 ◽

2021 ◽

Author(s):

Kelly L. Schoenbeck ◽

Mark A. Fiala ◽

Tanya M. Wildes

Keyword(s):

Older Adults ◽

Multiple Myeloma ◽

First Line ◽

First Line Therapy ◽

Line Therapy ◽

Falls In Older Adults

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Current Treatment Approaches to Newly Diagnosed Multiple Myeloma

Oncology Research and Treatment ◽

10.1159/000520504 ◽

2021 ◽

Vol 44 (12) ◽

pp. 690-699

Author(s):

Susanne Ghandili ◽

Katja C. Weisel ◽

Carsten Bokemeyer ◽

Lisa Beatrice Leypoldt

Keyword(s):

Multiple Myeloma ◽

Monoclonal Antibody ◽

Plasma Cell ◽

Cell Clone ◽

Unmet Need ◽

Continuous Treatment ◽

High Dose ◽

Line Treatment ◽

First Line ◽

First Line Treatment

Background: Multiple myeloma is a so far incurable malignant plasma cell disorder. During the past 2 decades, treatment paradigms substantially changed when novel drugs were introduced initially in treatment of relapsed disease and subsequently also in first-line treatment. Summary: Up to now, first-line treatment differs between patients initially classified as transplant eligible and those who are considered as nontransplant eligible. Transplant-eligible patients receive a primary proteasome inhibitor (PI)-based induction which is being combined with an immunomodulating agent and a CD38-directed monoclonal antibody followed by high-dose melphalan therapy and autologous stem cell transplantation with subsequent maintenance treatment with lenalidomide. Patients who are considered as nontransplant eligible receive upfront treatment preferentially with a continuous combination treatment either with a CD38-directed monoclonal antibody in combination with the immunomodulating agent lenalidomide or a lenalidomide-PI combination followed by lenalidomide maintenance. Key Messages: Primary goal of the initiated treatment is to induce a rapid and deep remission which ideally leads to an eradication of the residual plasma cell clone in sense of a minimal residual disease negativity. Achievement of long-term remission with limited toxicity despite continuous treatment strategies and maintenance or improvement of life-quality is key. Despite successful treatment options, specific difficult-to-treat subgroups, especially patients with high-risk myeloma remain with inferior prognosis and a clear unmet need for novel therapeutic strategies. Future concepts will evaluate cellular treatments and other innovative immunotherapies in first-line treatment in curative intention.

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Analysis of Falls in Older Adults with Multiple Myeloma Undergoing First-Line Therapy

Blood ◽

10.1182/blood-2019-129611 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5886-5886

Author(s):

Kelly L. Schoenbeck ◽

Tanya M. Wildes ◽

Mark A. Fiala

Keyword(s):

Older Adults ◽

Multiple Myeloma ◽

Peripheral Neuropathy ◽

First Line ◽

First Line Therapy ◽

Line Therapy ◽

Increased Risk ◽

Risk Of Falls ◽

Falls In Older Adults ◽

First Line Treatment

Background: Patients with multiple myeloma are frequently treated with bortezomib, a proteasome inhibitor, which is associated with treatment-related peripheral neuropathy. Older adults are at increased risk of falls compared to the general population, often leading to associated morbidity and mortality. While an association between peripheral neuropathy and falls in older adults is well-established, the relationship between bortezomib and falls in older multiple myeloma patients is unknown. Our primary aim was to determine if older patients with multiple myeloma treated with bortezomib as first-line therapy had an increased incidence of falls within the first 12 months after starting treatment. Our secondary aim was to assess the overall survival of patients who fell compared to those who did not among patients who lived more than 12 months after initiating treatment. Methods: We analyzed the SEER-Medicare database for all patients 65 years old or older diagnosed with multiple myeloma between 2007 and 2013 and were enrolled in fee-for-service Medicare part A, B and D plans. The patients' corresponding Medicare claims data were analyzed through 2014 for myeloma treatments, fall claims, and covariates of interest. The primary outcome was accidental falls (E880-E888) occurring between 14 days to 12 months after starting multiple myeloma treatment. First-line therapy was defined as any anti-myeloma treatment administered within 14 days of starting multiple myeloma treatment, with bortezomib treatment being the focal independent variable. Cox regression was performed to determine the relative risk of having a fall after controlling for other covariates. Patients who started bortezomib after first-line therapy were censored at time of bortezomib commencement. The survival analysis included only patients who survived more than 12 months of starting treatment to allow landmark analysis of falls in the first year. Results: Of 4,084 older adults with new multiple myeloma diagnoses undergoing first-line therapy, the median age was 75 (range 65-97) with 51% males. Bortezomib was used in first-line therapy for 2,052 (50%) patients, of which 157 (8%) patients experienced a fall within 12 months after starting treatment compared to 102 (5%) of patients not receiving bortezomib (p < 0.001). Bortezomib was associated with a 28% increase risk of falls (HR 1.29; 95% CI 1.00-1.65; p = 0.047). In multivariate analysis, bortezomib was not associated with an increased incidence of falls after controlling for age, gender, race, proxies for Charlson Comorbidity Index (CCI) and poor performance status, pre-existing peripheral neuropathy, falls within the 12 months prior to starting first-line myeloma treatment, depression, polypharmacy, and first-line treatment with lenalidomide (Table 1). Advancing age, history of fall(s), depression, and polypharmacy (defined as more than 10 unique prescription medications at initiation of first-line treatment), were all associated with an increased risk of falls, consistent with prior literature. In a landmark analysis of those who survived 12 months following the start of treatment, a fall was associated with a 26% increased risk of hazard for death (aHR 1.26; 95% CI 1.02-1.56; p = 0.033) after controlling for other covariates. The median OS of those with a fall was 35.7 months (95% CI 29.1-48.4) compared to 49.1 months (95% CI 47.1-52.8) for those without (p < 0.0001). Conclusion: In older adults with multiple myeloma, treatment with bortezomib was not associated with increased risk of a patient having a diagnostic code for falls. However, experiencing a fall within the year after starting treatment was associated with decreased overall survival. Limitations of the study include that the incidence of falls is likely underestimated in billing data, given prior data from our group showing a rate of self-reported falls of 26% in the year after diagnosis. Additional research, including prospective trials involving fall assessments, should be considered in older patients with multiple myeloma. Disclosures Wildes: Janssen: Research Funding; Carevive: Consultancy. Fiala:Incyte: Research Funding.

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Efficiency of lenalidomide, bortezomib and prednisone (RVP) in patients with newly diagnosed multiple myeloma

Oncohematology ◽

10.17650/1818-8346-2019-14-1-14-19 ◽

2019 ◽

Vol 14 (1) ◽

pp. 14-19 ◽

Cited By ~ 1

Author(s):

K. A. Belousov ◽

T. A. Mitina ◽

Yu. Yu. Chuksina ◽

A. K. Golenkov ◽

E. V. Kataeva ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

Renal Replacement Therapy ◽

Replacement Therapy ◽

Objective Response ◽

Hematological Toxicity ◽

Efficacy And Safety ◽

First Line ◽

First Line Therapy ◽

Line Therapy

Objective: to study the efficacy and safety of the antitumor RVP program (lenalidomide, bortezomib, prednisone) as a first-line therapy in patients with multiple myeloma (MM). Materials and methods. A prospective study involved 39 patients with MM (15 women, 24 men), median age 61 years (30–76 years). All patients had Durie–Salmon stage III disease. According to the paraprotein isotype variant, 19 patients (48.7 %) had Gk myeloma, 8 (20.5 %) had Gλ, 4 (10.2 %) – Ak, 1 – Aλ, 1 – Dk, 1 – paraproteinemia Bens-Jones k and 1 – Bens-Jones λ, 2 – Dλ, and 2 patients – nonsecreting MM. The average level of plasma cells in the bone marrow was 31.7 % (0.8–80.0 %). In 14 (35.8 %) patients there were plasmacytomas of various localization (spine, cranial bones, clavicle, pleura). Nine (23.0 %) patients had renal failure, requiring the start of renal replacement therapy. The average Karnovsky index in the study group was 50 %. All patients received RVP therapy (lenalidomide 25 mg in 1–14 days, bortezomib 1.3 mg subcutaneously in 1, 4, 8, 11 days, prednisolone 60 mg/m2; the interval between courses was 42 days) as the first line therapy. Evaluation of therapy efficacy, characterized by overall survival, objective response rates (the number of complete, very good partial and partial remissions) was performed after 6 treatment courses. Results. The median follow-up was 15 months; the median of overall survival was not achieved. Objective antitumor response achieved in 29 (74.3 %) patients, including complete remissions in 3 (7.6 %), very good partial remissions – in 7 (17.9 %), partial remissions – in 19 (48.7 %) patients. In 2 out of 9 patients who received renal replacement therapy, independence from dialysis therapy was achieved. Cases of III–IV stage hematological and non-hematological toxicity in the study were not noted. Conclusion. The antitumor RVP program showed high efficacy and safety as a first-line therapy in a non-selective group of patients, including those with a complicated MM course.

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The combination of thalidomide and intermediate-dose dexamethasone is an effective but toxic treatment for patients with primary amyloidosis (AL)

Blood ◽

10.1182/blood-2004-08-3231 ◽

2005 ◽

Vol 105 (7) ◽

pp. 2949-2951 ◽

Cited By ~ 144

Author(s):

Giovanni Palladini ◽

Vittorio Perfetti ◽

Stefano Perlini ◽

Laura Obici ◽

Francesca Lavatelli ◽

...

Keyword(s):

Multiple Myeloma ◽

Plasma Cells ◽

Primary Amyloidosis ◽

Line Treatment ◽

Second Line ◽

First Line ◽

First Line Therapy ◽

Line Therapy ◽

Symptomatic Bradycardia ◽

Intermediate Dose

AbstractBased on the efficacy of thalidomide in multiple myeloma and on its synergy with dexamethasone on myeloma plasma cells, we evaluated the combination of thalidomide (100 mg/d, with 100-mg increments every 2 weeks, up to 400 mg) and dexamethasone (20 mg on days 1-4) every 21 days in 31 patients with primary amyloidosis (AL) whose disease was refractory to or had relapsed after first-line therapy. Eleven (35%) patients tolerated the 400 mg/d thalidomide dose. Overall, 15 (48%) patients achieved hematologic response, with 6 (19%) complete remissions and 8 (26%) organ responses. Median time to response was 3.6 months (range, 2.5-8.0 months). Treatment-related toxicity was frequent (65%), and symptomatic bradycardia was a common (26%) adverse reaction. The combination of thalidomide and dexamethasone is rapidly effective and may represent a valuable second-line treatment for AL.

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Ig VH gene mutational patterns indicate different tumor cell status in human myeloma and monoclonal gammopathy of undetermined significance

Blood ◽

10.1182/blood.v87.2.746.bloodjournal872746 ◽

1996 ◽

Vol 87 (2) ◽

pp. 746-755 ◽

Cited By ~ 71

Author(s):

SS Sahota ◽

R Leo ◽

TJ Hamblin ◽

FK Stevenson

Keyword(s):

Multiple Myeloma ◽

Tumor Cell ◽

Plasma Cell ◽

Monoclonal Gammopathy ◽

Somatic Hypermutation ◽

Wide Spectrum ◽

Malignant Potential ◽

Gene Sequences ◽

Vh Gene ◽

Undetermined Significance

Plasma cell tumors display a wide spectrum of clinical progression, ranging from aggressive multiple myeloma to a benign form known as monoclonal gammopathy of undetermined significance (MGUS), which requires no treatment. Because both diseases involve mature Ig- secreting plasma cells, the reason for this variation in malignant behavior is unclear. However, assessment of malignant potential is desirable for choice of treatment protocols. Ig variable (VH) gene sequences analysis has previously shown the tumor cell of multiple myeloma to be postfollicular, with mutated homogeneous clonal sequences indicating no continuing exposure to the somatic hypermutation mechanism, and this was confirmed in 7 of 7 patients. Comparison of the VH gene sequences in the monoclonal cells in MGUS yielded a different result, with 3 of 7 patients demonstrating mutated heterogeneous sequences consistent with the tumor cells remaining under the influence of the mutator. In 1 of 3 of these patients, an IgM-positive precursor cell was identified that expressed heterogeneous VH sequences similar to those of the isotype-switched plasma cell. These results indicate that the clonal cells in MGUS differ from those in myeloma and suggest that the difference may reflect malignant potential.

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