An objective assessment in newly diagnosed multiple myeloma to avoid treatment complications and strengthen therapy adherence.

In heterogeneous multiple myeloma (MM) patients treatment decisions are challenging. The hypothesis was that adaptation of treatment intensity (dose reduction [DR] vs. none) according to an objective risk score (revised-myeloma comorbidity index [R-MCI]) rather than physician judgement alone may improve therapy efficacy and avoid toxicities. We performed this study in 250 consecutive MM patients who underwent a prospective fitness assessment at our center, after having received induction protocols based on physicians' judgement. DR, serious adverse events (SAE), response, progression-free survival (PFS) and overall survival (OS) were compared in fitness (fit, intermediate-fit, frail), age (<60, ≥70 years [y]) and therapy intensity subgroups at baseline and follow-up. Fit and <60 y patients were mostly treated with full intensity, whereas frail and ≥70 y patients usually received DR. Hematological and non-hematological SAE were more frequently seen in frail versus ≥70 y patients. Dose adaptations were mainly necessary in frail patients. OS and PFS were similar in fit and intermediate-fit but significantly worse in frail patients (P=0.0245/P<0.0001), whereas in age-based subgroups, OS and PFS differences did not reach significance (P=0.1362/P=0.0569). Non-hematological SAE were another negative predictor for impaired OS and PFS (P=0.0054/P=0.0021). In the follow-up performed at a median of 11 months after the first fitness assessment, the R-MCI improved or remained stable in 90% versus deteriorated in only 10% of patients. In conclusion, separation by R-MCI/frailty-defined subgroups was superior to age-based subgroups and can be used to improve tailored treatment. Fitter patients benefit from intensive therapies, whereas frail patients bear a need for initial DR.

Choosing the Right Therapy for Patients with Relapsed/Refractory Multiple Myeloma (RRMM) in Consideration of Patient-, Disease- and Treatment-Related Factors.

Treatment of relapsed/refractory multiple myeloma (RRMM) is more complex today due to the availability of novel therapeutic options, mostly applied as combination regimens. immunotherapy options have especially increased substantially, likewise the understanding that patient-, disease- and treatment-related factors should be considered at all stages of the disease. RRMM is based on definitions of the international myeloma working group (IMWG) and includes biochemical progression, such as paraprotein increase, or symptomatic relapse with CRAB criteria (hypercalcemia, renal impairment, anemia, bone lesions). When choosing RRMM-treatment, the biochemical markers for progression and severity of the disease, dynamic of disease relapse, type and number of prior therapy lines, including toxicity and underlying health status, need to be considered, and shared decision making should be pursued. Objectively characterizing health status via geriatric assessment (GA) at each multiple myeloma (MM) treatment decision point has been shown to be a better estimate than via age and comorbidities alone. The well-established national comprehensive cancer network, IMWG, European myeloma network and other national treatment algorithms consider these issues. Ideally, GA-based clinical trials should be supported in the future to choose wisely and efficaciously from available intervention and treatment options in often-older MM adults in order to further improve morbidity and mortality.

Comparison of the prognostic significance of 5 comorbidity scores and 12 functional tests in a prospective multiple myeloma patient cohort.

BACKGROUND: Because of the various therapeutic options available for multiple myeloma (MM), remarkable interest exists today in individualized therapeutic concepts based on patients' fitness. The main objectives of this study were to compare different comorbidity scores and functional tests with respect to their impact on survival (overall survival [OS] and progression-free survival [PFS]); develop a time-efficient, MM-specific functional assessment (FA); and evaluate changes in patients' FA during treatment. METHODS: The authors performed a prospective FA in 266 consecutive patients with MM at their initial diagnosis. This included 5 comorbidity scores and 12 commonly used geriatric functional tests. To evaluate changes in the course of treatment, the authors reassessed these 17 tests after ≥6 months. The entire analysis included 7327 FA tests. RESULTS: On the basis of univariate and multivariate Cox regression analyses, the authors identified 4 of the 17 evaluated scores and functional tests as most relevant: the Revised Myeloma Comorbidity Index (R-MCI), Activity of Daily Living (ADL), the Mini-Mental State Examination (MMSE), and the quality-of-life 12-Item Short Form Health Survey Physical Composite Scale (SF-12 PCS). These showed precise group differences for fit, (intermediate-fit), and frail patients in OS and PFS: the 3-year OS rates were 90%, 74%, and 43% via the R-MCI for fit, intermediate-fit, and frail patients, respectively (P = .0006); 80% and 66% via the ADL for fit and frail patients, respectively (P = .0159); 78% and 48% via the MMSE for fit and frail patients, respectively (P = .0001); and 86% and 66% via the SF-12 PCS for fit and frail patients, respectively (P = .0091). In follow-up analyses, 16 of 17 FA tests improved, mostly in younger patients (<70 years old) and responding patients (partial remission or better). CONCLUSIONS: Patients may recover from functional and physical limitations under applied MM therapy. The newly established MM-specific FA (via the R-MCI, ADL, MMSE, and SF-12 PCS) allows a precise evaluation of the prognosis and risk status in MM. Its use may improve treatment tolerability and should be validated to individualize MM treatment decisions in the future. LAY SUMMARY: The authors performed a prospective functional assessment (FA) in 266 consecutive patients with multiple myeloma at their initial diagnosis. On the basis of univariate and multivariate Cox regression analyses, the authors identified 4 of 17 initially evaluated scores and functional tests as most relevant: the Revised Myeloma Comorbidity Index, Activity of Daily Living, the Mini-Mental State Examination, and the quality-of-life 12-Item Short Form Health Survey Physical Composite Scale. The authors checked the stability of the final model by applying forward and stepwise selection. To evaluate changes in the course of treatment, they reassessed these 17 tests in 165 patients after ≥6 months: 16 of the 17 FA tests improved, mostly in younger patients (<70 years old) and responding patients (partial remission or better).

Avoiding chemotherapy prescribing errors: Analysis and innovative strategies.

BACKGROUND: At Freiburg University Medical Center, chemotherapy prescriptions are processed via a computerized physician order entry (CPOE) tool and clinically checked by a designated chemotherapy surveillance team. Any error detected is reported instantly, corrected, and prospectively recorded. The objective of the current study was to gain insight into the causes, potential consequences, and future preventability of chemotherapy prescribing errors. METHODS: A detailed analysis of 18,823 consecutive antineoplastic orders placed in 2013 through 2014 was performed. In cooperation with information technology (IT) specialists, the intercepted errors were analyzed for effective future prevention using IT measures. Potential error consequences were determined by case discussions between pharmacists and physicians. RESULTS: Within 24 months, a total of 406 chemotherapy prescribing errors were intercepted that affected 375 (2%) of the total orders. Errors were classified as clinically relevant in 279 of the chemotherapy orders (1.5%). In these cases, reduced therapeutic efficacy (0.44%), the need for increased monitoring (0.48%), prolonged hospital stay (0.55%), and fatality (0.02%) were avoided as potential consequences. The most efficient conventional measures for error prevention comprised checking the order history and patient's medical record, and a detailed knowledge of chemotherapy protocols. Of all the errors analyzed, 61% would be avoided through further software development. The improvements identified are implemented through a validated next-generation CPOE tool. CONCLUSIONS: The upgraded CPOE tool can be shared across other hospitals to raise safety standards and spread potential benefits across a wider patient population. The current analysis also highlighted that approximately 30% to 40% of errors cannot be avoided electronically. Therefore, pharmacovigilance initiatives remain indispensable.

GFR estimation in lenalidomide treatment of multiple myeloma patients: a prospective cohort study.

BACKGROUND: The estimated glomerular filtration rate (eGFR) is clinically used to approximate renal function and adapt drug dosage. Multiple myeloma is a hematological disease; its prognosis is largely influenced by renal function. We evaluated two commonly used GFR estimations, CKD-EPI and MDRD (CKD Epidemiology Collaboration; Modification of Diet in Renal Disease) in myeloma patients undergoing treatment with lenalidomide, a renally excreted immunomodulatory drug. METHODS: We prospectively studied 130 myeloma patients receiving lenalidomide treatment at our institution. At baseline and after 3 months, GFR estimations were performed based on the CKD-EPI and MDRD equations. We compared eGFR-dependent CKD staging and lenalidomide dosage assignments. RESULTS: Initially, most patients were classified as CKD stage I/II, using both equations. Comparison of baseline renal function via CKD-EPI and MDRD induced concordance of CKD staging in 83% of patients, while CKD-EPI improved CKD staging in 16% of patients (p = 0.11). CKD-EPI assigned 3% of patients to higher lenalidomide dosing as opposed to MDRD. Both equations showed improved eGFR after 3 months of lenalidomide treatment. CONCLUSIONS: In our multiple myeloma patient cohort, CKD-EPI and MDRD led to similar CKD staging with minor differences in lenalidomide dosage assignment. Consistent with previous studies, eGFR improved under lenalidomide treatment. To standardize GFR estimation in myeloma patients, we suggest using the CKD-EPI equation.

Pomalidomide.

Pomalidomide (originally CC-4047 or 3-amino-thalidomide) is a derivative of thalidomide that is antiangiogenic and also acts as immunomodulatory. Pomalidomide, the recent immunomodulatory agent (IMiD), has shown substantial in vitro antiproliferative and proapoptotic effects. In vivo studies have suggested limited cross-resistance between lenalidomide and pomalidomide. Moreover, pomalidomide achieved very convincing responses in relapsed and refractory multiple myeloma (RRMM) patients, including those, who are refractory to both lenalidomide and bortezomib. Since pomalidomide plus low-dose dexamethasone has shown better responses, progression-free survival (PFS) and overall survival (OS) than high-dose dexamethasone or pomalidomide alone, subsequent trials have pursued or are still investigating pomalidomide triplet combinations, using cyclophosphamide or other novel agents, such as proteasome inhibitors (PI: bortezomib, carfilzomib) or antibodies, like elotuzumab or daratumumab. Pomalidomide has also been assessed in AL amyloidosis, MPNs (myelofibrosis [MF]), Waldenstrom's macroglobulinemia, solid tumors (sarcoma, lung cancer), or HIV, and-for AL amyloidosis and MF-has already been proven to be remarkably active. Due to its potency, pomalidomide was approved for RRMM by the US Food and Drug Administration (FDA) and by the European Medicines Agency (EMA) in 2013 and for drug combination with low-dose dexamethasone in 2015. In June 2017, the FDA further expanded approval for pomalidomide in combination with daratumumab and low-dose dexamethasone for patients with RRMM.

Ruxolitinib.

Ruxolitinib, formerly known as INCB018424 or INC424, is a potent and selective oral inhibitor of Janus kinase (JAK) 1 and JAK2. Ruxolitinib has been approved for the treatment of myelofibrosis (MF) by the US Food and Drug Administration (FDA) in 2011 and by the European Medicines Agency (EMA) in 2012, followed by the approval for the treatment of hydroxyurea (HU)-resistant or -intolerant polycythemia vera (PV) in 2014. Both MF and PV are myeloproliferative neoplasms (MPNs) which are characterized by the aberrant activation of the JAK-STAT pathway. Clinically, MF features bone marrow fibrosis, splenomegaly, abnormal blood counts, and poor quality-of-life through associated symptoms. PV is characterized by the overproduction of primarily red blood cells (RBC), risk of thrombotic complications, and development of secondary MF. Ruxolitinib treatment results in a meaningful reduction in spleen size and symptom burden in the majority of MF patients and may also have a favorable effect on survival. In PV, ruxolitinib effectively controls the hematocrit and reduces splenomegaly. Since recently, ruxolitinib is also under investigation for the treatment of graft-versus-host disease (GvHD) after allogeneic hematopoietic stem cell transplantation (HSCT). Toxicities of ruxolitinib include myelosuppression, which results in dose-limiting thrombocytopenia and anemia, and viral reactivations. The metabolization of ruxolitinib through CYP3A4 needs to be considered particularly if co-administered with potent CYP3A4 inhibitors. Several further JAK inhibitors are currently under investigation for MPNs or other immuno-inflammatory diseases.

Paving the Way for Dose Banding of Chemotherapy: An Analytical Approach.

Background: In an interdepartmental cooperation, we investigated the feasibility and benefits of implementing dose banding of chemotherapy at our medical center. Based on this concept, chemotherapy doses are clustered into bands of similar dosage levels, thereby allowing the preproduction of frequently used standard doses of drugs, with sufficient physicochemical stability. Although established practice in the United Kingdom, there is little published evidence of its introduction elsewhere. Methods: We performed an analysis of local prescribing practice (22,310 chemotherapies) and identified gemcitabine, 5-fluorouracil, and carboplatin, among various others, as cytotoxic drugs suitable for dose banding. Results: First, we determined the physicochemical stability of the selected chemotherapy drugs during 12-weeks' storage by performing pH analysis and visual examination for color change or particles. No relevant changes were identified. Gemcitabine was selected for quantitative high-performance liquid chromatography analysis and we were able to show that ≥95% remained after 12 weeks' storage, in accordance with international guidelines. To simulate a worst case scenario, we performed microbiological stability testing of simulated cytotoxic compounding by replacing the cytotoxic drug with liquid media. Samples were incubated over defined storage time points (3, 6, and 12 weeks) and evaluated using the direct inoculation method. For the container integrity test, we deposited the samples into highly contaminated broth for 1 hour. Microbiological stability was demonstrated in both tests for the full storage period. Conclusions: Our data show that 12-weeks' storage of selected cytotoxic products is feasible from a microbiological perspective. Sterility of prepared products was maintained under extreme storage conditions. Gemcitabine content was in accordance with international guidelines after 12-weeks' storage. These results support the introduction of dose-banded gemcitabine products with the predicted advantages of optimized pharmacy workflow and reduced patient waiting times. We highlight the need for further research and consensus on the performance of purity analyses in dose-banded drug products.

A concise revised Myeloma Comorbidity Index as a valid prognostic instrument in a large cohort of 801 multiple myeloma patients.

With growing numbers of elderly multiple myeloma patients, reliable tools to assess their vulnerability are required. The objective of the analysis herein was to develop and validate an easy to use myeloma risk score (revised Myeloma Comorbidity Index) that allows for risk prediction of overall survival and progression-free survival differences in a large patient cohort. We conducted a comprehensive comorbidity, frailty and disability evaluation in 801 consecutive myeloma patients, including comorbidity risks obtained at diagnosis. The cohort was examined within a training and validation set. Multivariate analysis determined renal, lung and Karnofsky Performance Status impairment, frailty and age as significant risks for overall survival. These were combined in a weighted revised Myeloma Comorbidity Index, allowing for the identification of fit (revised Myeloma Comorbidity Index ≤3 [n=247, 30.8%]), intermediate-fit (revised Myeloma Comorbidity Index 4-6 [n=446, 55.7%]) and frail patients (revised Myeloma Comorbidity Index >6 [n=108, 13.5%]): these subgroups, confirmed via validation analysis, showed median overall survival rates of 10.1, 4.4 and 1.2 years, respectively. The revised Myeloma Comorbidity Index was compared to other commonly used comorbidity indices (Charlson Comorbidity Index, Hematopoietic Cell Transplantation-Specific Comorbidity Index, Kaplan-Feinstein Index): if each were divided in risk groups based on 25% and 75% quartiles, highest hazard ratios, best prediction and Brier scores were achieved with the revised Myeloma Comorbidity Index. The advantages of the revised Myeloma Comorbidity Index include its accurate assessment of patients' physical conditions and simple clinical applicability. We propose the revised Myeloma Comorbidity Index to be tested with the "reference" International Myeloma Working Group frailty score in multicenter analyses and future clinical trials. The study was registered at the German Clinical Trials Register (DRKS-00003868).

Geriatric assessment in multiple myeloma patients: validation of the International Myeloma Working Group (IMWG) score and comparison with other common comorbidity scores.

This first validation of the International Myeloma Working Group geriatric assessment in 125 newly diagnosed multiple myeloma patients was performed using the International Myeloma Working Group score based on age, the Charlson Comorbidity Index and cognitive and physical conditions (Activities of Daily Living / Instrumental Activities of Daily Living) to classify patients as fit, intermediate-fit or frail. We verified the International Myeloma Working Group score's impact on outcome, and whether additional tools complement it. Since our prior analyses determined renal, lung and Karnofsky performance impairment as multivariate risks, and the inclusion of frailty, age and cytogenetics complements this, we included the revised myeloma comorbidity index, the Charlson Comorbidity Index, the Hematopoietic Cell Transplantation-Comorbidity Index and the Kaplan-Feinstein Index in this assessment. Multivariate analysis confirmed cytogenetics, Activities of Daily Living, Instrumental Activities of Daily Living and the Charlson Comorbidity Index as risks: 3-year overall survival for fit, intermediate-fit and frail patients was 91%, 77% and 47%, respectively. Using the Charlson Comorbidity Index, the Hematopoietic Cell Transplantation-Comorbidity Index, the Kaplan-Feinstein Index and the revised Myeloma Comorbidity Index allowed us to define fit and frail patients with distinct progression-free and overall survival rates, with the most pronounced differences evidenced via the International Myeloma Working Group score, the Charlson Comorbidity Index and the revised Myeloma Comorbidity Index. Since the Charlson Comorbidity Index is included in the International Myeloma Working Group score, we propose the latter and the revised Myeloma Comorbidity Index for future frailty measurements. Both are useful instruments for identifying myeloma patients with a geriatric risk profile and have a strong prognostic value for functional decline and overall survival. The study was registered as: (clinicaltrials.gov Identifier: 00003686).

Large registry analysis to accurately define second malignancy rates and risks in a well-characterized cohort of 744 consecutive multiple myeloma patients followed-up for 25 years.

Additional malignancies in multiple myeloma patients after first-line and maintenance treatment have been observed, questioning whether specific risks exist. Second primary malignancies have also gained attention since randomized data showed associations to newer drugs. We have conducted this large registry analysis in 744 consecutive patients and analyzed: 1) frequency and onset of additional malignancies; and 2) second primary malignancy- and myeloma-specific risks. We assessed the frequency of additional malignancies in terms of host-, myeloma- and treatment-specific characteristics. To compare these risks, we estimated cumulative incidence rates for second malignancies and myeloma with Fine and Gray regression models taking into account competing risks. Additional malignancies were found in 118 patients: prior or synchronous malignancies in 63% and subsequent in 37%. Cumulative incidence rates for second malignancies were increased in IgG-myeloma and decreased in bortezomib-treated patients (P<0.05). Cumulative incidence rates for myeloma death were increased with higher stage and age, but decreased in IgG-subtypes and due to anti-myeloma treatment (P<0.05). Cytogenetics in patients acquiring second primary malignancies were predominantly favorable, suggesting that indolent myeloma and long disease latency may allow the manifestation of additional malignancies. An assessment of the Surveillance, Epidemiology, and End Result Program of the National Cancer Institute and our data with long-term follow up of 25 years confirmed a prevalence of second malignancy of 10% at 25 years, whereas death from myeloma decreased from 90% to 83%, respectively. Our important findings widen our knowledge of second malignancies and show that they are of increasing relevance as the prognosis in myeloma improves and mortality rates decrease.

Pomalidomide.

Pomalidomide (originally CC-4047 or 3-amino-thalidomide) is a derivative of thalidomide that is antiangiogenic and also acts as an immunomodulator. Pomalidomide, as the newest immunomodulatory agent (IMiD), has shown substantial in vitro antiproliferative and proapoptotic effects. In vivo studies have suggested limited cross-resistance between lenalidomide and pomalidomide, and the response of pomalidomide in relapsed and refractory (RR) multiple myeloma (MM) patients, including those who are refractory to both lenalidomide and bortezomib, has induced notable enthusiasm. Several studies have evaluated continuous (2 mg/day) or alternate (5 mg/2 day) dose schedules of pomalidomide, as well as 2 versus 4 mg schedules, and pomalidomide alone versus in combination with dexamethasone or other antimyeloma agents. Since pomalidomide plus low-dose dexamethasone has shown better responses, progression-free and overall survival than high-dose dexamethasone or pomalidomide alone, subsequent trials investigating pomalidomide combination therapy have been initiated. Among these trials combinations with alkylating agents (cyclophosphamide, bendamustin), anthracyclins (pegylated liposomal doxorubicin), proteasome inhibitors (bortezomib, carfilzomib), and various others can be found. Pomalidomide has also been assessed in AL amyloidosis, MPNs (myelofibrosis [MF]), Waldenstrom's macroglobulinemia, solid tumors (sarcoma, lung cancer), or HIV and--for AL amyloidosis and MF--has already proven remarkable activity. Due to its potency, pomalidomide was approved by the US Food and Drug Administration (FDA) for RRMM in 2/2013 and has also been approved by the European Medicines Agency (EMA).

Prevalence of iron overload vs iron deficiency in multiple myeloma: resembling or different from MDS--and stem cell transplant (SCT)--patients?

BACKGROUND: Most MM patients develop anemia with progression to symptomatic disease. Usually, this is normocytic/normochromic, with normal or low iron and elevated ferritin levels. Because ferritin levels alone do not correctly reflect iron stores, we performed a comprehensive analysis of iron parameters (iron, ferritin, transferrin, transferrin saturation [TRFS]) to more precisely assess patients' iron metabolism. PATIENTS AND METHODS: We analyzed: (1) the frequency of IO vs. ID in 136 consecutive MM patients; (2) the prognostic effect on progression-free (PFS) and overall survival (OS); and (3) specific risk groups according to patients' iron metabolism. RESULTS: Most patients had normal iron metabolism or ID: median iron, ferritin, transferrin, and TRFS values were 75 µg/dL, 446 µg/L, 195 mg/dL, and 26%, respectively. Ferritin levels of < 400 µg/L, 400 to 1000 µg/L, and > 1000 µg/L were observed in 46%, 30%, and 24%, and TRFS levels < 20%, 20% to 45%, and > 45% in 32%, 46%, and 22% of patients, respectively. When patients with modified (ID or IO) vs. normal iron metabolism were compared, laboratory parameters (prohormone of brain natriuretic peptide, estimated glomerular filtration rate, c-reactive protein, reflecting cardiac, renal, or infectious impairment), and PFS and OS appeared impaired with modified metabolism, albeit age- and disease-specific differences were insignificant. CONCLUSION: Normal iron metabolism and ID is more frequent in MM patients than IO. ID and IO correlate with organ impairment and impaired survival in MM. This knowledge should be incorporated into the design of future studies that will determine the benefit of iron supplementation with ID, and iron chelators with IO in MM.

Validation of the Freiburg Comorbidity Index in 466 multiple myeloma patients and combination with the international staging system are highly predictive for outcome.

BACKGROUND: The outcomes of MM patients vary considerably and depend on a variety of host- and disease-related risks. As yet, a comorbidity risk index in MM patients has neither been standardized nor validated. PATIENTS AND METHODS: We conducted an initial analysis in 127 MM patients and developed the FCI, validating it in an independent cohort of 466 MM patients. The FCI includes patients' Karnofsky Performance Status, renal and lung disease status. We compared the prognostic information of this validated FCI with established comorbidity indices (Hematopoietic Cell Transplantation-Specific Comorbidity Index and Kaplan Feinstein), the International Staging System (ISS), MM therapy, and age. RESULTS: Our validation confirmed that patients with 0, 1, or 2 to 3 FCI risk factors display significantly different overall survival (OS) of not reached, 86, and 39 months, respectively (P < .0001). Via multivariate analysis including the FCI, ISS, therapy, and age, the FCI retained its independent prognostic significance (P < .0015). The combination of the FCI and ISS allowed definition of 3 distinct subgroups with low-risk (FCI 0 and ISS I-II), intermediate-risk (all remaining), and high-risk (FCI 1-3 and ISS III) with OS probabilities at 5-years of 85%, 74%, and 42%, respectively (P < .0001). CONCLUSION: Our validation analysis demonstrated that the FCI remains a reliable comorbidity index, is simpler to generate than other available comorbidity scores, and contributes valuable information to the ISS. Their combination allows the definition of low-, intermediate-, and high-risk patients. These results advocate use of the FCI in future prospective studies and might guide personalized treatment strategies.