Original Study
Connect MM Registry: The Importance of Establishing Baseline Disease Characteristics Robert M. Rifkin,1 Rafat Abonour,2 Howard Terebelo,3 Jatin J. Shah,4 Cristina Gasparetto,5 James Hardin,6 Shankar Srinivasan,7 Rosanna Ricafort,7 Yasir Nagarwala,7 Brian G.M. Durie8 Abstract In this analysis, we focused on the importance of establishing baseline characteristics in multiple myeloma patients in the Connect MM registry. Variations were observed in the percentage of reported baseline data. Creating solid records of baseline patient disease characteristics using suggested National Comprehensive Cancer Network diagnostic work-up and International Myeloma Working Group criteria provides a foundation for monitoring disease progression and response to treatment. Background: Connect MM is the first and largest observational, noninterventional, prospective registry of patients newly diagnosed with multiple myeloma (NDMM) in the United States. It collects longitudinal data on patients within clinical practice including patients in clinical trials. Patients and Methods: Of the 1513 patients enrolled, 1493 were protocol-eligible. Results: Median age was 67 years, 81.9% (1223/1493) were Caucasian, and 57.2% (854/1493) were male. Of these patients, 26.5% (232/877) were International Staging System stage I, 34.9% (306/877) stage II, and 38.7% (339/877) stage III. Eastern Cooperative Oncology Group performance status of 0/1/2 were reported in 96.6% (1017/ 1053). Clonal plasma cells > 10% were found in 91.6% (1282/1399) of patients and M-component in 98.8% (1343/1359). Hypercalcemia was present in 7.3% (108/1481) of patients, serum creatinine > 2 mg/dL in 18.3% (271/1484), anemia in 45.1% (673/1493), and bone involvement in 76.7% (1143/1490). Of the 15 National Comprehensive Cancer Network (NCCN) recommended diagnostic tests, a median of 12 were performed. Lactate dehydrogenase assessment, serum free light chain ratio, and immunofixation were reported in 38.4% (574/1493), 62.1% (927/1493), and 66% (985/1493) of patients, respectively. Quantitative immunoglobulin, b-2 microglobulin, and protein electrophoresis (serum or urine) were reported in 72.3% (1080/1493), 74.1% (1107/1493), and 78.0% (1164/1493) of patients, respectively. Bone marrow biopsy was reported in 92.2% (1376/1493), but conventional cytogenetic and fluorescence in situ hybridization analysis were reported in only 63.2% (944/1493) and 59.8% (893/1493) of patients, respectively. A high-risk cytogenetic profile (according to International Myeloma Working Group [IMWG] criteria) was found in 16.9% (253/1493). Conclusion: This analysis provides insight into the demographic and disease characteristics of NDMM patients in a range of clinical practices. Creating solid records of baseline patient disease characteristics using suggested NCCN diagnostic workup and IMWG criteria provides a foundation for monitoring disease progression and response to treatment. Clinical Lymphoma, Myeloma & Leukemia, Vol. 15, No. 6, 368-76 ª 2015 Elsevier Inc. All rights reserved. Keywords: Baseline Disease Characteristics, Diagnostics, IMWG, Multiple Myeloma, NCCN Guidelines
Introduction Multiple Myeloma Multiple myeloma (MM) is a hematologic disorder characterized by a proliferation of malignant plasma cells and production of 1 US Oncology Research, The Woodlands, TX and Rocky Mountain Cancer Centers, Denver, CO 2 Indiana University Simon Cancer Center, Indianapolis, IN 3 Newland Medical Associates, Novi, MI 4 M.D. Anderson Cancer Center, Houston, TX 5 Duke University Medical Center, Durham, NC 6 University of South Carolina, Columbia, SC 7 Celgene Corporation, Summit, NJ 8 Cedars-Sinai Comprehensive Cancer Center, Los Angeles, CA
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monoclonal paraprotein (M-protein).1-3 MM is a debilitating condition, often accompanied by lytic bone lesions, bone pain, fractures, and renal insufficiency. Bone disease and recurrent infections produce a variety of symptoms, which ultimately result in end-organ Submitted: Sep 23, 2014; Revised: Dec 1, 2014; Accepted: Dec 6, 2014; Epub: Dec 11, 2014
Address for correspondence: Robert M. Rifkin, MD, US Oncology Research, The Woodlands, TX and Rocky Mountain Cancer Centers, 1800 Williams St, Suite 200, Denver, CO 80218 E-mail contact: [email protected]
2152-2650/$ - see frontmatter ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clml.2014.12.002
damage/dysfunction. Plasma cell dyscrasias (early to late stage) comprise a spectrum of conditions ranging in severity, from monoclonal gammopathy of unknown significance (MGUS), smoldering (or asymptomatic) MM, to the more advanced stage of active or symptomatic MM.4 The National Comprehensive Cancer Network (NCCN) and the International Myeloma Working Group (IMWG) recommend a battery of diagnostic and prognostic tests for any patient with suspected myeloma.5,6 After testing, a formal diagnosis should be made using the universally accepted IMWG diagnostic criteria.6 The IMWG guidelines were first proposed in 2003, and distinguish between MGUS, asymptomatic MM, and symptomatic MM on the basis of M-protein and bone marrow clonal plasma cell concentrations, and evidence of end-organ damage as follows: MGUS, M-protein < 30 g/L, bone marrow clonal plasma cells < 10%, with no evidence of MM; smoldering (asymptomatic) MM, M-protein 30 g/L and/or bone marrow plasma clonal cells 10%, but no related end-organ damage (typically manifested by increased calcium, renal insufficiency, anemia, or bone lesions [CRAB] criteria); and symptomatic MM, same as for asymptomatic MM, but with evidence of end-organ damage.2 In addition, a subgroup of patients with asymptomatic disease, but a high risk of progression within 2 years of diagnosis has recently been identified.7,8 Recommendations for the management of these patients are still evolving.7 Risk assignment based on cytogenetic features is an influential factor in myeloma management and the IMWG guidelines have recently been updated to reflect current advances in therapeutic practice.9 In its most recent statement, the IMWG proposes well defined and easily applicable risk categories, and suggest their use as the gold standard in all clinical trials and to form the basis of development of more complex prognostic systems.9
work-up5 and application of the IMWG criteria9 as part of the initial diagnostic characterization of NDMM. We highlight the importance of establishing a good foundation of baseline data for in-depth understanding of the disease evolution in the individual patient, with the ultimate goal to improve treatment of NDMM patients in the future.
Patients and Methods Study Design The Connect MM Registry was established in September 2009 and is sponsored by Celgene. Participation in the registry is voluntary; patients can withdraw at any time without penalty and without affecting their subsequent medical care. No planned investigational agent, prescribed treatment regimen, or intervention is mandated while participating in the registry. Enrolled NDMM patients were treated according to the clinical practice at each study site; therapies were determined by the treating physician according to his/her clinical judgment.
Patients Patients were enrolled between September 28, 2009 and December 14, 2011 at 259 US sites including academic and military/Veteran Administration clinical centers. Individuals aged 18 years who were diagnosed with symptomatic MM within the previous 2 months were eligible for inclusion in the study; there were no exclusion criteria. The registry definition of symptomatic MM followed the IMWG criteria.2 Patient follow-up was initially for 5 years, but was extended to 8 years from enrollment, as per protocol amendment (April 28, 2011), or until early discontinuation (due to death, withdrawal of consent, loss to follow-up, or registry termination). Patients who discontinued participation continued to be monitored for survival until death, loss to follow-up, or eventual withdrawal of consent.
Connect MM Registry The Connect MM Registry (ClinicalTrials.gov identifier: NCT01081028) is an ongoing, prospective, longitudinal, multicenter, observational research initiative, which was established to explore the natural history and management of patients newly diagnosed with MM (NDMM) in US clinical practice (community-, academic-, and government-based hematology and oncology centers). This ongoing study plans to enroll 3000 eligible patients. The primary objective of the Connect MM Registry is to describe patterns of care of common first-line treatment regimens and subsequent therapeutic strategies in NDMM patients in clinical practice. The secondary objectives of the registry are to: (1) provide insight into treatment regimens and therapy sequences in clinical practice in relation to clinical outcomes (response, overall survival, progression-free survival); (2) describe any differences in effectiveness associated with different treatment regimens, including common first-line regimens, subsequent therapeutic strategies, and regional differences; (3) describe the health-related quality of life (HRQoL) of NDMM patients, and explore the association of treatment regimens/ sequence and clinical outcomes with HRQoL. By providing information to clinicians regarding the management and outcomes of NDMM, it is anticipated the data will inform patient care. Here, we describe the baseline demographic and disease characteristics of NDMM patients enrolled in the Connect MM Registry. Moreover, we describe usage of the NCCN suggested diagnostic
Data Collection The following baseline data were collected during the enrollment visit and entered into an electronic case report form (eCRF): date of informed consent; demographic characteristics; relevant medical history; Eastern Cooperative Oncology Group (ECOG) performance status (PS) score; diagnosis information (eg, date of diagnosis, staging, and cytogenetic testing); results of laboratory testing, if performed as part of routine care; current MM-related supportive concomitant medications and procedures; clinical trial participation; and lines of therapy received (including the initial treatment regimen prescribed). Staging for NDMM was recorded using the International Staging System (ISS), the DurieeSalmon staging system, or both systems.10,11 Follow-up data were collected every 3 months during registry participation, and included: ECOG PS score; treatment status (response assessment [evaluated by the physician]; initial or subsequent MM lines of therapy; reason for treatment discontinuation/ change; any chemotherapeutic conditioning/transplant[s]/maintenance); current MM-related supportive concomitant medications and procedures; health care resource utilization; existence and results of select laboratory testing (if performed); participation in any clinical trial; occurrence of second primary malignancies; and date of registry discontinuation. All data are as reported on the eCRF. A modified frailty index algorithm, based on the recently presented geriatric assessment, was used to stratify patients as fit, unfit,
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Connect MM Registry and Baseline Disease Characteristics or frail.12 Not all of the parameters included in the assessment were collected in the Connect MM Registry and so a modified version was developed. The algorithm categorized patients as: fit, those aged < 80 years, Karnofsky PS score of 80% (ECOG PS score of 0-1), and had no comorbidities; unfit, patients aged > 80 years and/ or Karnofsky PS score of 60% to 80% (ECOG PS score 2), and/or the presence of 1 comorbidity; or frail, patients aged > 80 years, Karnofsky PS score of < 60% (ECOG PS score 3-4), and/or the presence of 2 comorbidities.
Statistical Analysis Outputs were evaluated using standard statistical methods for observational studies. No a priori formal sample size calculations were performed, because the population size was expected to be sufficiently large to address known biases. The following variables are collected and analyzed for all patients in the Connect MM Registry: demographic characteristics (age, sex, race, ethnicity, geographic region of residence, and medical insurance), baseline characteristics, diagnostics, and risk factors, ISS staging (calculated and collected), initial work fields (as recommended in the NCCN guidelines), and frequencies of imaging modalities. All demographic and baseline disease characteristics are presented using descriptive statistics. Missing data can be more prevalent in registries than in controlled trials.13 In this analysis, missing data (not specified or not provided) in the eCRF were not removed from the denominators of entries in some tables and, therefore, some groups of subpopulation percentages do not add to 100%.
requirements; 5 had asymptomatic MM; 5 had unspecified MM; 1 was unable to participate; and 1 withdrew) leaving 1493 enrolled protocol-eligible patients (Figure 1). Of these 1493 patients, 1407 satisfied the CRAB criteria. Although 86 patients were reported not to meet the CRAB criteria, their demographic and clinical characteristics were similar to those who did (data not shown). Of these 86 patients, 79 were reported to be receiving or had received treatment. Most of these patients (93.7%; 74 of 79) were classified as having smoldering MM and 38.0% (30 of 79) as having > 60% bone marrow clonal plasma cells, suggesting that this group of patients represented an ‘ultra-high risk’ subset, characterized by a propensity for rapid, early progression that prompted therapy.14,15
Demographic Characteristics at Baseline At baseline, patient median age was 67 years (range, 24-94 years), 57.2% (854 of 1493) of patients were male, and 81.9% (1223 of 1493) were Caucasian (Table 1). Age < 65 years was reported in 43.5% (649 of 1493) of patients, with 30.5% (456 of 1493) of patients aged 65 to < 75 years, and 26.0% (388 of 1493) of patients aged 75 years. Of the 1493 patients, 70.5% (1053 of 1493) were from the Midwest or Southern regions of the United States (Figure 2). Across the cohort, 81.1% (1211 of 1493) of patients were enrolled in community clinics, 17.6% (263 of 1493) in academic centers, and 1.3% (19 of 1493) in military/Veteran Administration facilities. All patients had medical insurance, with approximately half of them insured by Medicare and half by private coverage (Table 1).
Disease Characteristics
Results Patients Between September 2009 and December 2011, 1513 patients consented and enrolled into the Connect MM Registry. A total of 20 patients were deemed ineligible (8 did not meet protocol Figure 1 Patient Flow
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Abbreviation: CRAB ¼ Calcium, Renal Insufficiency, Anemia, and Bone Lesions.
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All patients were reported to have active/symptomatic myeloma (Table 2). Nonsecretory MM was reported in 11 patients (0.7%). Abnormal levels of serum free light chain (FLC) were reported in 90.1% (264 of 293). Patients with a documented history of MGUS, smoldering myeloma, or asymptomatic myeloma were uncommon
Robert M. Rifkin et al Table 1 Demographic Characteristics, Insurance Status, and Institutional Setting of Protocol-Eligible Patients (n [ 1493) Demographic Characteristic
Value
Age Median (range), years
67.0 (24.0-94.0)
91% of patients. In 9.8% (146 of 1493) of patients, SPEP or UPEP, quantitative immunoglobulins, or sFLCr analysis was not performed. When taking into account qualitative immunofixation studies, only a small proportion of patients, 5% (75 of 1493), did not have SPEP/UPEP, quantitative immunoglobulins, sFLCr, or immunofixation studies performed. A comparison between the academic and community site settings showed a similar pattern of reported NCCN recommended tests (Figure 3). Similar patterns were also observed in patients who did not meet CRAB criteria, and in patients who did or did not receive initial therapy (data not shown).
Cytogenetic and Fluorescence In Situ Hybridization Analysis Bone marrow biopsy and aspiration were reported in 92.2% (1376 of 1493) and 88.3% (1318 of 1493) of patients, respectively. Almost all patients 96.9% (1446 of 1493) had either biopsy or aspirate performed. A small proportion of patients, 3.1% (47 of 1493), had neither performed. In 8.6% (128 of 1493) of patients, a biopsy but not an aspirate was reported. Conventional cytogenetic analysis (karyotyping) was reported in 63.2% (944 of 1493) of patients. Cytogenetic analysis was performed in 944 patients; 5.8% (55 of 944) were not specified and 2.5% (24 of 944) failed. Cytogenetic abnormalities were reported in 27.6% (261 of 944) of tested patients with 2.9% (76 of 261) having del(13).
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Connect MM Registry and Baseline Disease Characteristics Figure 2 Geographic Distribution of Patients
Cytogenetic risk was defined according to IMWG criteria.9 Low risk was defined as age < 55 years and ISS stage I to II, with absence of t(4;14), del(17p13), and/or þ1q21 cytogenetic abnormalities. High risk was defined as age 55 years and ISS stage II to III, with t(4;14) or del(17p13) cytogenetic abnormalities. Standard-risk patients were those in neither the low-risk nor high-risk categories. Of the analyzed patients, 6.0% (90 of 1493) were classified as low risk, 39.7% (592 of 1493) as standard risk, and 16.9% (253 of 1493) as high risk. Fluorescence in situ hybridization analysis (FISH) analysis was reported for 59.8% (893 of 1493) of patients and abnormalities were reported in 64.7% (578 of 893) of tested patients. Deletions of chromosomes 13 (rb1 locus) and 17 (p53 locus) were reported in 19.4% (173 of 893) and 11.3% (101 of 893) of tested patients, respectively. Translocations of 14q32, involving the loci t(11;14), t(4;14), and t(14;16), were reported in 14.4% (129 of 893), 6.3% (56 of 893), and 4.0% (36 of 893) of tested patients, respectively. Other abnormalities were observed in 34.8% (311 of 893) of patients.
Modified Frailty Index Scoring Using the modified frailty algorithm, 29.0% (433 of 1493) of patients were categorized as fit, 42.9% (641 of 1493) as unfit, and 28.1% (419 of 1493) as frail.
Radiographic Imaging Surveys/Scans
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Skeletal surveys, as recommended by the NCCN for the detection of lytic lesions, were reported in 84.8% (1266 of 1493) of patients. Magnetic resonance imaging (MRI) and computed tomography (CT) scans, which are often indicated but not mandated, were reported to be performed in 37.2% (556 of 1493) and in 42.1% (629 of 1493) patients, respectively. Positron emission
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tomography (PET)/CT scans or PET scans (also not mandated) were reported in 9.3% (139 of 1493) and 2.4% (36 of 1493) of patients, respectively. By report, 3.9% (58 of 1493) of patients had neither skeletal survey, MRI, CT, nor PET/CT scans performed at baseline.
Discussion This study presents the baseline patient characteristics of 1493 patients enrolled in the Connect MM Registry, the largest prospective observational MM registry in the United States. Of the 15 NCCN recommended tests, 80% were performed at diagnosis (a median of 12). Bone marrow biopsy was reported in 92.2% of patients, but conventional cytogenetic and FISH analyses were reported in only 63.2% and 59.8% of patients, respectively. This analysis provides insight into the demographic and disease characteristics of NDMM patients and the pattern of initial diagnostic work-up seen across a range of clinical practices. Thorough diagnostic work-up for accurate disease assessment and risk stratification is important for tailoring treatment approaches and has recently been recognized as an educational need in MM patient care.16 The median age of patients (67 years) and proportion of male patients (57.2%) included in the Connect MM Registry agrees with other reports describing NDMM patients.17-21 Most of the patients in this study were Caucasian (81.9%)17,22; however, because the disease generally occurs approximately twice as frequently in African-Americans than in Caucasians,23 the racial characteristics in the study might reflect the smaller overall percentage of AfricanAmerican individuals in the general population. Moreover, it might also suggest an underrepresentation of African-American individuals in research studies.24-26 In a pooled analysis of 869 elderly NDMM patients participating in clinical trials, a geriatric assessment to risk-stratify
Robert M. Rifkin et al Table 3 Summary of Diagnostic Criteria (N [ 1493)
Table 2 Disease Characteristics Value Disease Characteristic (N [ 1493) Active/symptomatic myeloma Nonsecretory multiple myeloma
Normal
Value
Bone Marrow Plasmacytosis (n [ 1399) 1493 (100) 11 (0.7)
Serum Free Light Chain Level (n [ 293) Abnormal
Diagnostic Criteria 10% Clonal cells
1282 (91.6)
30%.16,31 Altogether, a complete baseline diagnostic work-up is essential to optimize the treatment plan and monitor response in NDMM patients. In an era in which the implementation of electronic medical records is evolving, inclusion of NCCN mandated fields would help drive their use. In 96.9% of patients, data on bone marrow biopsy or aspirate were collected. In 8.6% of patients, a biopsy was reported but not an aspirate. In these patients, it is conceivable that, although the diagnostic procedure was performed, there might have been an inability to aspirate marrow, due to hypercellularity, fibrosis, or faulty technique. Additionally, only 60% of these patients had subsequent FISH/cytogenetics analyses on file. This might be explained by either having an insufficient number of cells to conduct the tests or simply by not ordering these tests, because it might not be widely adopted for use in initial treatment selection because results are not back in time to inform treatment strategies. Of the tested patients, 16.9% had high-risk cytogenetic abnormalities as defined according to IMWG criteria. Using FISH analysis, deletions of chromosome 13 (rb1 locus) and 17 (p53 locus) were found in 19.4% and 11.3% of tested patients, respectively.
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Chromosome 14 translocations of t(11;14), t(4;14), and t(14;16) were found in 14.4%, 6.3%, and 4.0% of patients, respectively. Our findings are similar to other studies in NDMM patients,18,19,32 showing that the enrolled patients in the Connect MM Registry are representative for NDMM patients. Appropriate risk stratification is important for therapeutic decision-making.9 The Connect MM Registry is the largest and first, to our knowledge, population-based study to be conducted in NDMM patients in the United States. A Korean hospital-based registry examined the survival outcomes of 3209 MM patients as they related to baseline clinical and laboratory disease characteristics.33 In the Korean registry, the median age was 61 years (range, 32-91 years), 54.7% were male, 17.9% had ISS stage I disease, 71% had ISS stage II to III disease, and 45.5% had an ECOG PS score of 0 to 1. Moreover, the cytogenetic abnormalities profile was similar to the Connect MM Registry.18,19 Data from the Swedish Myeloma registry have recently been reported.34 The registry contains 2494 patients (median age, 70 [male] and 73 [female] years) enrolled between 2008 and 2011. Of patients with symptomatic disease, osteolytic lesions or compression fractures were reported in 76% of patients. Although some general commonalities might be identified, direct comparisons across different registries should be approached with caution due to differences in patient populations, data collection methodology, and completeness of data. In 76.7% of patients in the Connect MM Registry, bone involvement was reported; compression fractures are common clinical symptoms in the disease, highlighting the importance of performing skeletal surveys. Imaging techniques include MRI, CT, and PET/CT scans. The importance of MRI as a more sensitive screening method can play a role in developing future response criteria together with CRAB. Advancement in imaging techniques can provide clinicians with data on the extent of bone marrow infiltration and bone disease, and assessing response.35 Data analysis using information collected in large-volume registries such as the Connect MM Registry can help improve patient outcomes. Because registries reflect clinical practice, what we learn from them can help identify best practices and areas of improvement. Furthermore, observational data from registries can be used to study rare diseases, rare exposures, and rare outcomes. Registries might be used to assess regional or national differences in diseases and treatment practices,36 and can also provide useful information as an alternative and short-term solution to data collection in expensive randomized controlled trials.13 Missing data might be more of an issue with registries compared with randomized trials and can be a limitation in associated data analyses,13 where other methods must be used to maximize case ascertainment.37 For example, in this study, the reported lack of complete blood cell count (although 95.5% of patients reported a blood draw) and routine staging analysis might reflect limitations of data entry and reporting associated with registries, as opposed to tests not actually being conducted. In the Connect MM, a possible reason for missing or not reported data might be that some patients might have been referred to study sites from external institutions. The baseline data might not have been readily available when the case report forms were completed—our protocol inclusion criteria allowed enrollment of patients with newly diagnosed symptomatic MM within 2 months of initial diagnosis.
Robert M. Rifkin et al Figure 3 National Comprehensive Cancer Network Evaluation Forms Workup: Academic and Community Sites
Abbreviations: BUN ¼ blood urea nitrogen; FISH ¼ fluorescence in situ hybridization; LDH ¼ lactate dehydrogenase; RBC ¼ red blood cell; WBC ¼ white blood cell.
Care must be taken not to overinterpret registries beyond their original purpose. Generalizability of each MM registry, local health care system differences, and different follow-up intervals must also be taken into account when using registry data.13,36
Conclusion The Connect MM Registry is the first and largest prospective MM disease registry in the United States. This initial analysis provides insight into the demographic and baseline disease characteristics of patients with MM seen in community, academic, and government practice. Baseline testing of key factors required for accurate diagnosis and assessment, and adequate monitoring of MM patients to guide therapy decisions appears to be variable, and suggests an unmet educational need.16 This is represents an opportunity for improvement in the quality of care in this patient population, which can be fulfilled with continued education and training.
The demographic and clinical characteristics of NDMM patients
in the Connect MM Registry will provide insight to physicians regarding what they can expect in clinical practice. The data support the notion that a thorough baseline diagnostic work-up of NDMM patients should be performed to assess disease progression and response to treatment.
Acknowledgments The Connect MM Registry is sponsored and funded by Celgene Corporation. The authors received editorial support from Michael van der Veer, PhD, from Excerpta Medica, in the preparation of this report, which was funded by Celgene Corporation. The authors were fully responsible for all content and editorial decisions for this report.
Disclosure Clinical Practice Points The demographic and clinical characteristics of NDMM patients
are documented in clinical trials. Established evidence-based recommendations exist for the diag-
nosis of MM. The demographic and disease characteristics of NDMM patients
seen in clinical practice (academic, community, and government) are presented. Use of the NCCN suggested tests for initial diagnostic workup varies in clinical practice.
RMR reports consultancy for Celgene Corporation, Millenium Pharmaceuticals, Takeda Pharmaceutical Company, and Onyx Pharmaceuticals; RA reports Speakers’ bureau for Celgene Corporation, Millenium Pharmaceuticals, and Onyx Pharmaceuticals; HT reports a Member of the Board of Directors for Celgene Corporation; JJS reports honoraria, consultancy, and research funding from Celgene Corporation, Millenium Pharmaceuticals, Onyx Pharmaceuticals, Novartis, and Array Biopharma; CG reports consultancy and honoraria from Celgene, and other remuneration from Novartis; JH reports consultancy from Celgene Corporation; SS,
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Connect MM Registry and Baseline Disease Characteristics RR, and YN report employment at Celgene Corporation; and BGMD reports consultancy for Amgen.
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20. Moreau P, San Miguel J, Ludwig H, et al. Multiple myeloma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2013; 24(suppl 6):vi133-7. 21. Facon T, Dimopopoulos MA, Dispenzieri A, et al. Initial phase 3 results of the FIRST (Frontline Investigation of Lenalidomide þ Dexamethasone Versus Standard Thalidomide) trial (MM-020/IFM 07 01) in newly diagnosed multiple myeloma (NDMM) patients (pts) ineligible for stem cell transplantation (SCT). Blood 2013; 122: abstract 2. 22. Turesson I, Velez R, Kristinsson SY, Landgren O. Patterns of improved survival in patients with multiple myeloma in the twenty-first century: a population-based study. J Clin Oncol 2010; 28:830-4. 23. Landgren O, Graubard BI, Katzmann JA, et al. Racial disparities in the prevalence of monoclonal gammopathies: a population-based study of 12,482 persons from the National Health and Nutritional Examination Survey. Leukemia 2014; 28:1537-42. 24. Branson RD, Davis K Jr, Butler KL. African Americans’ participation in clinical research: importance, barriers, and solutions. Am J Surg 2007; 193:32-9, discussion 40. 25. Lang R, Kelkar VA, Byrd JR, et al. African American participation in health-related research studies: indicators for effective recruitment. J Public Health Manag Pract 2013; 19:110-8. 26. Byrd GS, Edwards CL, Kelkar VA, et al. Recruiting intergenerational African American males for biomedical research studies: a major research challenge. J Natl Med Assoc 2011; 103:480-7. 27. Durie BG, Harousseau JL, Miguel JS, et al. International uniform response criteria for multiple myeloma. Leukemia 2006; 20:1467-73. 28. Dispenzieri A, Kyle R, Merlini G, et al. International Myeloma Working Group guidelines for serum-free light chain analysis in multiple myeloma and related disorders. Leukemia 2009; 23:215-24. 29. Bagaria SP, Ashman JB, Daugherty LC, et al. Compliance with National Comprehensive Cancer Network guidelines in the use of radiation therapy for extremity and superficial trunk soft tissue sarcoma in the United States. J Surg Oncol 2014; 109:633-8. 30. Stuckey A, Febbraro T, Laprise J, et al. Adherence patterns to National Comprehensive Cancer Network Guidelines for referral of women with breast cancer to genetics professionals. Am J Clin Oncol, Published online April 5, 2014; doi: 10.1097/COC.0000000000000073. 31. Visser BC, Ma Y, Zak Y, et al. Failure to comply with NCCN guidelines for the management of pancreatic cancer compromises outcomes. HPB (Oxford) 2012; 14: 539-47. 32. Kumar S, Fonseca R, Ketterling RP, et al. Trisomies in multiple myeloma: impact on survival in patients with high-risk cytogenetics. Blood 2012; 119:2100-5. 33. Tan D, Chng WJ, Chou T, et al. Management of multiple myeloma in Asia: resource-stratified guidelines. Lancet Oncol 2013; 14:e571-81. 34. Blimark C, Holmberg E, Juliusson G, et al. Real world data in myeloma: experiences from the Swedish population-based registry on 2494 myeloma patients diagnosed 2008-2011. Blood 2013; 122: abstract 1972. 35. Dimopoulos M, Terpos E, Comenzo RL, et al. International myeloma working group consensus statement and guidelines regarding the current role of imaging techniques in the diagnosis and monitoring of multiple myeloma. Leukemia 2009; 23:1545-56. 36. Yoshida K, Radner H, Kavanaugh A, et al. Use of data from multiple registries in studying biologic discontinuation: challenges and opportunities. Clin Exp Rheumatol 2013; 31(suppl 78):S28-32. 37. Counsel CE, Collie DA, Grant R. Limitations of using a cancer registry to identify incident primary intracranial tumours. J Neurol Neurosurg Psychiatry 1997; 63:94-7.
Connect MM Registry: The Importance of Establishing Baseline Disease Characteristics Robert M. Rifkin,1 Rafat Abonour,2 Howard Terebelo,3 Jatin J. Shah,4 Cristina Gasparetto,5 James Hardin,6 Shankar Srinivasan,7 Rosanna Ricafort,7 Yasir Nagarwala,7 Brian G.M. Durie8 Abstract In this analysis, we focused on the importance of establishing baseline characteristics in multiple myeloma patients in the Connect MM registry. Variations were observed in the percentage of reported baseline data. Creating solid records of baseline patient disease characteristics using suggested National Comprehensive Cancer Network diagnostic work-up and International Myeloma Working Group criteria provides a foundation for monitoring disease progression and response to treatment. Background: Connect MM is the first and largest observational, noninterventional, prospective registry of patients newly diagnosed with multiple myeloma (NDMM) in the United States. It collects longitudinal data on patients within clinical practice including patients in clinical trials. Patients and Methods: Of the 1513 patients enrolled, 1493 were protocol-eligible. Results: Median age was 67 years, 81.9% (1223/1493) were Caucasian, and 57.2% (854/1493) were male. Of these patients, 26.5% (232/877) were International Staging System stage I, 34.9% (306/877) stage II, and 38.7% (339/877) stage III. Eastern Cooperative Oncology Group performance status of 0/1/2 were reported in 96.6% (1017/ 1053). Clonal plasma cells > 10% were found in 91.6% (1282/1399) of patients and M-component in 98.8% (1343/1359). Hypercalcemia was present in 7.3% (108/1481) of patients, serum creatinine > 2 mg/dL in 18.3% (271/1484), anemia in 45.1% (673/1493), and bone involvement in 76.7% (1143/1490). Of the 15 National Comprehensive Cancer Network (NCCN) recommended diagnostic tests, a median of 12 were performed. Lactate dehydrogenase assessment, serum free light chain ratio, and immunofixation were reported in 38.4% (574/1493), 62.1% (927/1493), and 66% (985/1493) of patients, respectively. Quantitative immunoglobulin, b-2 microglobulin, and protein electrophoresis (serum or urine) were reported in 72.3% (1080/1493), 74.1% (1107/1493), and 78.0% (1164/1493) of patients, respectively. Bone marrow biopsy was reported in 92.2% (1376/1493), but conventional cytogenetic and fluorescence in situ hybridization analysis were reported in only 63.2% (944/1493) and 59.8% (893/1493) of patients, respectively. A high-risk cytogenetic profile (according to International Myeloma Working Group [IMWG] criteria) was found in 16.9% (253/1493). Conclusion: This analysis provides insight into the demographic and disease characteristics of NDMM patients in a range of clinical practices. Creating solid records of baseline patient disease characteristics using suggested NCCN diagnostic workup and IMWG criteria provides a foundation for monitoring disease progression and response to treatment. Clinical Lymphoma, Myeloma & Leukemia, Vol. 15, No. 6, 368-76 ª 2015 Elsevier Inc. All rights reserved. Keywords: Baseline Disease Characteristics, Diagnostics, IMWG, Multiple Myeloma, NCCN Guidelines
Introduction Multiple Myeloma Multiple myeloma (MM) is a hematologic disorder characterized by a proliferation of malignant plasma cells and production of 1 US Oncology Research, The Woodlands, TX and Rocky Mountain Cancer Centers, Denver, CO 2 Indiana University Simon Cancer Center, Indianapolis, IN 3 Newland Medical Associates, Novi, MI 4 M.D. Anderson Cancer Center, Houston, TX 5 Duke University Medical Center, Durham, NC 6 University of South Carolina, Columbia, SC 7 Celgene Corporation, Summit, NJ 8 Cedars-Sinai Comprehensive Cancer Center, Los Angeles, CA
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monoclonal paraprotein (M-protein).1-3 MM is a debilitating condition, often accompanied by lytic bone lesions, bone pain, fractures, and renal insufficiency. Bone disease and recurrent infections produce a variety of symptoms, which ultimately result in end-organ Submitted: Sep 23, 2014; Revised: Dec 1, 2014; Accepted: Dec 6, 2014; Epub: Dec 11, 2014
Address for correspondence: Robert M. Rifkin, MD, US Oncology Research, The Woodlands, TX and Rocky Mountain Cancer Centers, 1800 Williams St, Suite 200, Denver, CO 80218 E-mail contact: [email protected]
2152-2650/$ - see frontmatter ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clml.2014.12.002
damage/dysfunction. Plasma cell dyscrasias (early to late stage) comprise a spectrum of conditions ranging in severity, from monoclonal gammopathy of unknown significance (MGUS), smoldering (or asymptomatic) MM, to the more advanced stage of active or symptomatic MM.4 The National Comprehensive Cancer Network (NCCN) and the International Myeloma Working Group (IMWG) recommend a battery of diagnostic and prognostic tests for any patient with suspected myeloma.5,6 After testing, a formal diagnosis should be made using the universally accepted IMWG diagnostic criteria.6 The IMWG guidelines were first proposed in 2003, and distinguish between MGUS, asymptomatic MM, and symptomatic MM on the basis of M-protein and bone marrow clonal plasma cell concentrations, and evidence of end-organ damage as follows: MGUS, M-protein < 30 g/L, bone marrow clonal plasma cells < 10%, with no evidence of MM; smoldering (asymptomatic) MM, M-protein 30 g/L and/or bone marrow plasma clonal cells 10%, but no related end-organ damage (typically manifested by increased calcium, renal insufficiency, anemia, or bone lesions [CRAB] criteria); and symptomatic MM, same as for asymptomatic MM, but with evidence of end-organ damage.2 In addition, a subgroup of patients with asymptomatic disease, but a high risk of progression within 2 years of diagnosis has recently been identified.7,8 Recommendations for the management of these patients are still evolving.7 Risk assignment based on cytogenetic features is an influential factor in myeloma management and the IMWG guidelines have recently been updated to reflect current advances in therapeutic practice.9 In its most recent statement, the IMWG proposes well defined and easily applicable risk categories, and suggest their use as the gold standard in all clinical trials and to form the basis of development of more complex prognostic systems.9
work-up5 and application of the IMWG criteria9 as part of the initial diagnostic characterization of NDMM. We highlight the importance of establishing a good foundation of baseline data for in-depth understanding of the disease evolution in the individual patient, with the ultimate goal to improve treatment of NDMM patients in the future.
Patients and Methods Study Design The Connect MM Registry was established in September 2009 and is sponsored by Celgene. Participation in the registry is voluntary; patients can withdraw at any time without penalty and without affecting their subsequent medical care. No planned investigational agent, prescribed treatment regimen, or intervention is mandated while participating in the registry. Enrolled NDMM patients were treated according to the clinical practice at each study site; therapies were determined by the treating physician according to his/her clinical judgment.
Patients Patients were enrolled between September 28, 2009 and December 14, 2011 at 259 US sites including academic and military/Veteran Administration clinical centers. Individuals aged 18 years who were diagnosed with symptomatic MM within the previous 2 months were eligible for inclusion in the study; there were no exclusion criteria. The registry definition of symptomatic MM followed the IMWG criteria.2 Patient follow-up was initially for 5 years, but was extended to 8 years from enrollment, as per protocol amendment (April 28, 2011), or until early discontinuation (due to death, withdrawal of consent, loss to follow-up, or registry termination). Patients who discontinued participation continued to be monitored for survival until death, loss to follow-up, or eventual withdrawal of consent.
Connect MM Registry The Connect MM Registry (ClinicalTrials.gov identifier: NCT01081028) is an ongoing, prospective, longitudinal, multicenter, observational research initiative, which was established to explore the natural history and management of patients newly diagnosed with MM (NDMM) in US clinical practice (community-, academic-, and government-based hematology and oncology centers). This ongoing study plans to enroll 3000 eligible patients. The primary objective of the Connect MM Registry is to describe patterns of care of common first-line treatment regimens and subsequent therapeutic strategies in NDMM patients in clinical practice. The secondary objectives of the registry are to: (1) provide insight into treatment regimens and therapy sequences in clinical practice in relation to clinical outcomes (response, overall survival, progression-free survival); (2) describe any differences in effectiveness associated with different treatment regimens, including common first-line regimens, subsequent therapeutic strategies, and regional differences; (3) describe the health-related quality of life (HRQoL) of NDMM patients, and explore the association of treatment regimens/ sequence and clinical outcomes with HRQoL. By providing information to clinicians regarding the management and outcomes of NDMM, it is anticipated the data will inform patient care. Here, we describe the baseline demographic and disease characteristics of NDMM patients enrolled in the Connect MM Registry. Moreover, we describe usage of the NCCN suggested diagnostic
Data Collection The following baseline data were collected during the enrollment visit and entered into an electronic case report form (eCRF): date of informed consent; demographic characteristics; relevant medical history; Eastern Cooperative Oncology Group (ECOG) performance status (PS) score; diagnosis information (eg, date of diagnosis, staging, and cytogenetic testing); results of laboratory testing, if performed as part of routine care; current MM-related supportive concomitant medications and procedures; clinical trial participation; and lines of therapy received (including the initial treatment regimen prescribed). Staging for NDMM was recorded using the International Staging System (ISS), the DurieeSalmon staging system, or both systems.10,11 Follow-up data were collected every 3 months during registry participation, and included: ECOG PS score; treatment status (response assessment [evaluated by the physician]; initial or subsequent MM lines of therapy; reason for treatment discontinuation/ change; any chemotherapeutic conditioning/transplant[s]/maintenance); current MM-related supportive concomitant medications and procedures; health care resource utilization; existence and results of select laboratory testing (if performed); participation in any clinical trial; occurrence of second primary malignancies; and date of registry discontinuation. All data are as reported on the eCRF. A modified frailty index algorithm, based on the recently presented geriatric assessment, was used to stratify patients as fit, unfit,
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Connect MM Registry and Baseline Disease Characteristics or frail.12 Not all of the parameters included in the assessment were collected in the Connect MM Registry and so a modified version was developed. The algorithm categorized patients as: fit, those aged < 80 years, Karnofsky PS score of 80% (ECOG PS score of 0-1), and had no comorbidities; unfit, patients aged > 80 years and/ or Karnofsky PS score of 60% to 80% (ECOG PS score 2), and/or the presence of 1 comorbidity; or frail, patients aged > 80 years, Karnofsky PS score of < 60% (ECOG PS score 3-4), and/or the presence of 2 comorbidities.
Statistical Analysis Outputs were evaluated using standard statistical methods for observational studies. No a priori formal sample size calculations were performed, because the population size was expected to be sufficiently large to address known biases. The following variables are collected and analyzed for all patients in the Connect MM Registry: demographic characteristics (age, sex, race, ethnicity, geographic region of residence, and medical insurance), baseline characteristics, diagnostics, and risk factors, ISS staging (calculated and collected), initial work fields (as recommended in the NCCN guidelines), and frequencies of imaging modalities. All demographic and baseline disease characteristics are presented using descriptive statistics. Missing data can be more prevalent in registries than in controlled trials.13 In this analysis, missing data (not specified or not provided) in the eCRF were not removed from the denominators of entries in some tables and, therefore, some groups of subpopulation percentages do not add to 100%.
requirements; 5 had asymptomatic MM; 5 had unspecified MM; 1 was unable to participate; and 1 withdrew) leaving 1493 enrolled protocol-eligible patients (Figure 1). Of these 1493 patients, 1407 satisfied the CRAB criteria. Although 86 patients were reported not to meet the CRAB criteria, their demographic and clinical characteristics were similar to those who did (data not shown). Of these 86 patients, 79 were reported to be receiving or had received treatment. Most of these patients (93.7%; 74 of 79) were classified as having smoldering MM and 38.0% (30 of 79) as having > 60% bone marrow clonal plasma cells, suggesting that this group of patients represented an ‘ultra-high risk’ subset, characterized by a propensity for rapid, early progression that prompted therapy.14,15
Demographic Characteristics at Baseline At baseline, patient median age was 67 years (range, 24-94 years), 57.2% (854 of 1493) of patients were male, and 81.9% (1223 of 1493) were Caucasian (Table 1). Age < 65 years was reported in 43.5% (649 of 1493) of patients, with 30.5% (456 of 1493) of patients aged 65 to < 75 years, and 26.0% (388 of 1493) of patients aged 75 years. Of the 1493 patients, 70.5% (1053 of 1493) were from the Midwest or Southern regions of the United States (Figure 2). Across the cohort, 81.1% (1211 of 1493) of patients were enrolled in community clinics, 17.6% (263 of 1493) in academic centers, and 1.3% (19 of 1493) in military/Veteran Administration facilities. All patients had medical insurance, with approximately half of them insured by Medicare and half by private coverage (Table 1).
Disease Characteristics
Results Patients Between September 2009 and December 2011, 1513 patients consented and enrolled into the Connect MM Registry. A total of 20 patients were deemed ineligible (8 did not meet protocol Figure 1 Patient Flow
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Abbreviation: CRAB ¼ Calcium, Renal Insufficiency, Anemia, and Bone Lesions.
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All patients were reported to have active/symptomatic myeloma (Table 2). Nonsecretory MM was reported in 11 patients (0.7%). Abnormal levels of serum free light chain (FLC) were reported in 90.1% (264 of 293). Patients with a documented history of MGUS, smoldering myeloma, or asymptomatic myeloma were uncommon
Robert M. Rifkin et al Table 1 Demographic Characteristics, Insurance Status, and Institutional Setting of Protocol-Eligible Patients (n [ 1493) Demographic Characteristic
Value
Age Median (range), years
67.0 (24.0-94.0)
91% of patients. In 9.8% (146 of 1493) of patients, SPEP or UPEP, quantitative immunoglobulins, or sFLCr analysis was not performed. When taking into account qualitative immunofixation studies, only a small proportion of patients, 5% (75 of 1493), did not have SPEP/UPEP, quantitative immunoglobulins, sFLCr, or immunofixation studies performed. A comparison between the academic and community site settings showed a similar pattern of reported NCCN recommended tests (Figure 3). Similar patterns were also observed in patients who did not meet CRAB criteria, and in patients who did or did not receive initial therapy (data not shown).
Cytogenetic and Fluorescence In Situ Hybridization Analysis Bone marrow biopsy and aspiration were reported in 92.2% (1376 of 1493) and 88.3% (1318 of 1493) of patients, respectively. Almost all patients 96.9% (1446 of 1493) had either biopsy or aspirate performed. A small proportion of patients, 3.1% (47 of 1493), had neither performed. In 8.6% (128 of 1493) of patients, a biopsy but not an aspirate was reported. Conventional cytogenetic analysis (karyotyping) was reported in 63.2% (944 of 1493) of patients. Cytogenetic analysis was performed in 944 patients; 5.8% (55 of 944) were not specified and 2.5% (24 of 944) failed. Cytogenetic abnormalities were reported in 27.6% (261 of 944) of tested patients with 2.9% (76 of 261) having del(13).
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Connect MM Registry and Baseline Disease Characteristics Figure 2 Geographic Distribution of Patients
Cytogenetic risk was defined according to IMWG criteria.9 Low risk was defined as age < 55 years and ISS stage I to II, with absence of t(4;14), del(17p13), and/or þ1q21 cytogenetic abnormalities. High risk was defined as age 55 years and ISS stage II to III, with t(4;14) or del(17p13) cytogenetic abnormalities. Standard-risk patients were those in neither the low-risk nor high-risk categories. Of the analyzed patients, 6.0% (90 of 1493) were classified as low risk, 39.7% (592 of 1493) as standard risk, and 16.9% (253 of 1493) as high risk. Fluorescence in situ hybridization analysis (FISH) analysis was reported for 59.8% (893 of 1493) of patients and abnormalities were reported in 64.7% (578 of 893) of tested patients. Deletions of chromosomes 13 (rb1 locus) and 17 (p53 locus) were reported in 19.4% (173 of 893) and 11.3% (101 of 893) of tested patients, respectively. Translocations of 14q32, involving the loci t(11;14), t(4;14), and t(14;16), were reported in 14.4% (129 of 893), 6.3% (56 of 893), and 4.0% (36 of 893) of tested patients, respectively. Other abnormalities were observed in 34.8% (311 of 893) of patients.
Modified Frailty Index Scoring Using the modified frailty algorithm, 29.0% (433 of 1493) of patients were categorized as fit, 42.9% (641 of 1493) as unfit, and 28.1% (419 of 1493) as frail.
Radiographic Imaging Surveys/Scans
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Skeletal surveys, as recommended by the NCCN for the detection of lytic lesions, were reported in 84.8% (1266 of 1493) of patients. Magnetic resonance imaging (MRI) and computed tomography (CT) scans, which are often indicated but not mandated, were reported to be performed in 37.2% (556 of 1493) and in 42.1% (629 of 1493) patients, respectively. Positron emission
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tomography (PET)/CT scans or PET scans (also not mandated) were reported in 9.3% (139 of 1493) and 2.4% (36 of 1493) of patients, respectively. By report, 3.9% (58 of 1493) of patients had neither skeletal survey, MRI, CT, nor PET/CT scans performed at baseline.
Discussion This study presents the baseline patient characteristics of 1493 patients enrolled in the Connect MM Registry, the largest prospective observational MM registry in the United States. Of the 15 NCCN recommended tests, 80% were performed at diagnosis (a median of 12). Bone marrow biopsy was reported in 92.2% of patients, but conventional cytogenetic and FISH analyses were reported in only 63.2% and 59.8% of patients, respectively. This analysis provides insight into the demographic and disease characteristics of NDMM patients and the pattern of initial diagnostic work-up seen across a range of clinical practices. Thorough diagnostic work-up for accurate disease assessment and risk stratification is important for tailoring treatment approaches and has recently been recognized as an educational need in MM patient care.16 The median age of patients (67 years) and proportion of male patients (57.2%) included in the Connect MM Registry agrees with other reports describing NDMM patients.17-21 Most of the patients in this study were Caucasian (81.9%)17,22; however, because the disease generally occurs approximately twice as frequently in African-Americans than in Caucasians,23 the racial characteristics in the study might reflect the smaller overall percentage of AfricanAmerican individuals in the general population. Moreover, it might also suggest an underrepresentation of African-American individuals in research studies.24-26 In a pooled analysis of 869 elderly NDMM patients participating in clinical trials, a geriatric assessment to risk-stratify
Robert M. Rifkin et al Table 3 Summary of Diagnostic Criteria (N [ 1493)
Table 2 Disease Characteristics Value Disease Characteristic (N [ 1493) Active/symptomatic myeloma Nonsecretory multiple myeloma
Normal
Value
Bone Marrow Plasmacytosis (n [ 1399) 1493 (100) 11 (0.7)
Serum Free Light Chain Level (n [ 293) Abnormal
Diagnostic Criteria 10% Clonal cells
1282 (91.6)
30%.16,31 Altogether, a complete baseline diagnostic work-up is essential to optimize the treatment plan and monitor response in NDMM patients. In an era in which the implementation of electronic medical records is evolving, inclusion of NCCN mandated fields would help drive their use. In 96.9% of patients, data on bone marrow biopsy or aspirate were collected. In 8.6% of patients, a biopsy was reported but not an aspirate. In these patients, it is conceivable that, although the diagnostic procedure was performed, there might have been an inability to aspirate marrow, due to hypercellularity, fibrosis, or faulty technique. Additionally, only 60% of these patients had subsequent FISH/cytogenetics analyses on file. This might be explained by either having an insufficient number of cells to conduct the tests or simply by not ordering these tests, because it might not be widely adopted for use in initial treatment selection because results are not back in time to inform treatment strategies. Of the tested patients, 16.9% had high-risk cytogenetic abnormalities as defined according to IMWG criteria. Using FISH analysis, deletions of chromosome 13 (rb1 locus) and 17 (p53 locus) were found in 19.4% and 11.3% of tested patients, respectively.
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Chromosome 14 translocations of t(11;14), t(4;14), and t(14;16) were found in 14.4%, 6.3%, and 4.0% of patients, respectively. Our findings are similar to other studies in NDMM patients,18,19,32 showing that the enrolled patients in the Connect MM Registry are representative for NDMM patients. Appropriate risk stratification is important for therapeutic decision-making.9 The Connect MM Registry is the largest and first, to our knowledge, population-based study to be conducted in NDMM patients in the United States. A Korean hospital-based registry examined the survival outcomes of 3209 MM patients as they related to baseline clinical and laboratory disease characteristics.33 In the Korean registry, the median age was 61 years (range, 32-91 years), 54.7% were male, 17.9% had ISS stage I disease, 71% had ISS stage II to III disease, and 45.5% had an ECOG PS score of 0 to 1. Moreover, the cytogenetic abnormalities profile was similar to the Connect MM Registry.18,19 Data from the Swedish Myeloma registry have recently been reported.34 The registry contains 2494 patients (median age, 70 [male] and 73 [female] years) enrolled between 2008 and 2011. Of patients with symptomatic disease, osteolytic lesions or compression fractures were reported in 76% of patients. Although some general commonalities might be identified, direct comparisons across different registries should be approached with caution due to differences in patient populations, data collection methodology, and completeness of data. In 76.7% of patients in the Connect MM Registry, bone involvement was reported; compression fractures are common clinical symptoms in the disease, highlighting the importance of performing skeletal surveys. Imaging techniques include MRI, CT, and PET/CT scans. The importance of MRI as a more sensitive screening method can play a role in developing future response criteria together with CRAB. Advancement in imaging techniques can provide clinicians with data on the extent of bone marrow infiltration and bone disease, and assessing response.35 Data analysis using information collected in large-volume registries such as the Connect MM Registry can help improve patient outcomes. Because registries reflect clinical practice, what we learn from them can help identify best practices and areas of improvement. Furthermore, observational data from registries can be used to study rare diseases, rare exposures, and rare outcomes. Registries might be used to assess regional or national differences in diseases and treatment practices,36 and can also provide useful information as an alternative and short-term solution to data collection in expensive randomized controlled trials.13 Missing data might be more of an issue with registries compared with randomized trials and can be a limitation in associated data analyses,13 where other methods must be used to maximize case ascertainment.37 For example, in this study, the reported lack of complete blood cell count (although 95.5% of patients reported a blood draw) and routine staging analysis might reflect limitations of data entry and reporting associated with registries, as opposed to tests not actually being conducted. In the Connect MM, a possible reason for missing or not reported data might be that some patients might have been referred to study sites from external institutions. The baseline data might not have been readily available when the case report forms were completed—our protocol inclusion criteria allowed enrollment of patients with newly diagnosed symptomatic MM within 2 months of initial diagnosis.
Robert M. Rifkin et al Figure 3 National Comprehensive Cancer Network Evaluation Forms Workup: Academic and Community Sites
Abbreviations: BUN ¼ blood urea nitrogen; FISH ¼ fluorescence in situ hybridization; LDH ¼ lactate dehydrogenase; RBC ¼ red blood cell; WBC ¼ white blood cell.
Care must be taken not to overinterpret registries beyond their original purpose. Generalizability of each MM registry, local health care system differences, and different follow-up intervals must also be taken into account when using registry data.13,36
Conclusion The Connect MM Registry is the first and largest prospective MM disease registry in the United States. This initial analysis provides insight into the demographic and baseline disease characteristics of patients with MM seen in community, academic, and government practice. Baseline testing of key factors required for accurate diagnosis and assessment, and adequate monitoring of MM patients to guide therapy decisions appears to be variable, and suggests an unmet educational need.16 This is represents an opportunity for improvement in the quality of care in this patient population, which can be fulfilled with continued education and training.
The demographic and clinical characteristics of NDMM patients
in the Connect MM Registry will provide insight to physicians regarding what they can expect in clinical practice. The data support the notion that a thorough baseline diagnostic work-up of NDMM patients should be performed to assess disease progression and response to treatment.
Acknowledgments The Connect MM Registry is sponsored and funded by Celgene Corporation. The authors received editorial support from Michael van der Veer, PhD, from Excerpta Medica, in the preparation of this report, which was funded by Celgene Corporation. The authors were fully responsible for all content and editorial decisions for this report.
Disclosure Clinical Practice Points The demographic and clinical characteristics of NDMM patients
are documented in clinical trials. Established evidence-based recommendations exist for the diag-
nosis of MM. The demographic and disease characteristics of NDMM patients
seen in clinical practice (academic, community, and government) are presented. Use of the NCCN suggested tests for initial diagnostic workup varies in clinical practice.
RMR reports consultancy for Celgene Corporation, Millenium Pharmaceuticals, Takeda Pharmaceutical Company, and Onyx Pharmaceuticals; RA reports Speakers’ bureau for Celgene Corporation, Millenium Pharmaceuticals, and Onyx Pharmaceuticals; HT reports a Member of the Board of Directors for Celgene Corporation; JJS reports honoraria, consultancy, and research funding from Celgene Corporation, Millenium Pharmaceuticals, Onyx Pharmaceuticals, Novartis, and Array Biopharma; CG reports consultancy and honoraria from Celgene, and other remuneration from Novartis; JH reports consultancy from Celgene Corporation; SS,
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Connect MM Registry and Baseline Disease Characteristics RR, and YN report employment at Celgene Corporation; and BGMD reports consultancy for Amgen.
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