This article reports on the first-ever case of IgD MM documented in ASL BT thanks to the use of new technologies and the development of diagnostic algorithms.
IgD-mediated MM is rare hematologic disease affecting predominantly male patients with a mean age of 59 years (54–65 years) [14]. The diagnosis of this disease is complex because of the low titer of the paraprotein involved (0–10 mg/dL) and its half-life is2.8 days [1, 14], so it is often not detectable on electrophoretic trace but only in sIFE [15, 16]. Unfortunately, some laboratories do not provide for the use of anti-IgD antisera in sIFE, so the risk of IgD MM being misdiagnosed or confused with Light Chain Deposition Disease (LCDD) is high, as evidenced by the case of our patient for whom tests performed at outside laboratories had shown the presence of MC consisting of λ chains only. In order to avoid interpretative errors, as recommended in literature [16, 17], whenever sIFE shows only the monoclonal κ or λ band after immunotyping with standard anti IgG, IgA, IgM, κ and λ antisera, it is necessary to process the test sample with anti IgD, IgE, λ free and κ, with a serum/diluent ratio of 1:1.5. In our experience, unlike what has been reported by other authors, we consider the use of a diluent in order to optimize gel electrophoretic run and avoid false positives [18]. This procedure has allowed us to detect 5 patients with IgD MC isotype and 2 with IgE isotype in the last 4 years.
In the case illustrated, the severe renal impairment required a rapid measurement of BJP concentration [19–23], that is a useful parameter for evaluating the efficacy of therapeutic schemes. Therefore, a new operative procedure, schematized in the flow chart in Fig. 4, for performing urine electrophoresis on the 24-hour urine collection in order to quantify BJP and/or complete MC by densitometric scanning of the electrophoretic run on agarose gel was agreed upon between the Units.
This clinical case presented at diagnosis with some features typical of IgD MM: light chain λ subtype [1, 9], normocytic normochromic anemia [1, 2], Bence Jones proteinuria and impaired renal function [14], 1q21 amplification [24], osteolytic lesions, generalized weakness, fatigue and bone pain, marked decrease in uninvolved immunoglobulin classes [1, 2] and also the clinical signs of aggressive disease [14]. From a biochemical point of view, hypercalcemia, elevated creatinine levels, LDH, β2M and CRP concentrations are detected more often in IgD MM compared with all other subtypes [17, 25].
The biochemical and hematological parameters of the patient of our clinical case were collected from the diagnosis up to the present day (Table 2). In the 56 months observation period, in particular, we recorded consistently high values of Crea (reference range 0.45–1.25 mg/dL) and β2M (reference range 1,09–2.53 mg/L), decreased eGFR (11 measurements, data not shown, reference range 95–150 ml/min), proteinuria (reference value < 150 mg/24h), CRP slightly altered (reference value < 0.80 mg/dL), anemia (reference range Hb 13.7–17.5 g/dL) and immunoparesis (suppression of uninvolved immunoglobulins): the measurement of serum immunoglobulins revealed decreased concentrations of IgA (reference range 70–400 mg/dL) and IgM (reference range 40–230 mg/dL) in all determinations performed, while IgG serum level (reference range 700–1600 mg/dL) was within the reference range in only two out of eight assays. Unlike what is reported in literature, in this clinical case calcium serum levels (reference range 8.8–10.2 mg/dL) were always normal. In addition, LDH, alkaline phosphatase (ALP) and aspartate and alanine transaminase (AST and ALT) were always within the reference range and the serum ferritin level was always above the upper limit (reference range 10–300 ng/mL) (data not shown).
Table 2
Main hematochemical tests in follow-up
Date | Ca (mg/dL) | Crea (mg/L) | CRP (mg/dL) | Hb (g/dL) | β2M (ng/L) | IgG (mg/dL) | IgA (mg/dL) | IgM (mg/dL) |
2019-10-02 | 9,3 | 2,86 | 1,01 | 9,8 | 8,55 | 702 | 54 | 22 |
2019-10-14 | NP | 2,81 | NP | 8.7 | NP | NP | NP | NP |
2019-12-03 | 9,4 | 2,01 | NP | 9,5 | NP | NP | NP | NP |
2019-12-17 | 9,4 | 1,98 | 4,87 | 9,3 | 5,35 | 524 | 36 | < 25 |
2020-01-07 | 9,4 | 1,76 | 0,38 | 10,4 | 4,7 | 592 | 38 | < 22 |
2020-01-21 | 9,5 | 1,76 | 0,21 | NP | NP | NP | NP | NP |
2020-02-11 | 9,5 | 1,7 | NP | 10.9 | NP | NP | NP | NP |
2020-03-18 | 9,9 | 1,83 | NP | 11.8 | NP | NP | NP | NP |
2020-04-22 | 9,8 | 1,84 | NP | 11,2 | NP | NP | NP | NP |
2020-05-27 | 9,4 | 1,9 | NP | 11 | NP | NP | NP | NP |
2020-06-25 | 9,5 | 1,84 | NP | 11,1 | NP | NP | NP | NP |
2020-07-27 | NP | 1,97 | NP | 11 | NP | NP | NP | NP |
2020-09-29 | 9,4 | 1,7 | NP | 12,2 | NP | 693 | 47 | 15 |
2020-11-18 | 9,7 | 1,65 | NP | 12,4 | 3,67 | 720 | 59 | 24 |
2021-01-27 | 9,7 | 1,72 | 0,71 | 13 | 3,79 | 819 | 76 | 30 |
2021-03-01 | 9,4 | 1,71 | NP | 13,1 | NP | NP | NP | NP |
2021-04-29 | 9,5 | 1,91 | NP | 13,7 | NP | NP | NP | NP |
2021-05-31 | 9,4 | 2,34 | NP | 13,1 | NP | NP | NP | NP |
2021-07-07 | 10,2 | 2,85 | NP | 12,7 | NP | NP | NP | NP |
2021-07-17 | 9,4 | 2,47 | NP | 12,2 | 5,53 | 883 | 71 | 21 |
2021-09-03 | NP | NP | NP | 13.1 | NP | NP | NP | NP |
2021-09-10 | 9 | 1,89 | NP | NP | NP | NP | NP | NP |
2021-10-11 | NP | 1,88 | NP | 13 | NP | NP | NP | NP |
2021-10-14 | 9,5 | 1,62 | NP | 12.4 | NP | NP | NP | NP |
2021-11-08 | 9,6 | 1,98 | NP | 12.4 | NP | NP | NP | NP |
2021-11-24 | 9 | 2,06 | NP | 12 | NP | NP | NP | NP |
2021-12-20 | 9,4 | 2,22 | NP | 10.5 | NP | NP | NP | NP |
2022-01-17 | 9,3 | 1,68 | 6,51 | 11.3 | 5,44 | 411 | 7 | 22 |
2022-02-14 | 8,7 | 1,62 | NP | 11 | NP | NP | NP | NP |
2022-02-28 | 8,1 | 1,74 | NP | 12.1 | NP | NP | NP | NP |
2022-03-14 | 9,3 | 1,51 | 0,72 | 12.5 | 4,05 | 376 | 8 | < 22 |
2022-04-05 | 8,5 | 1,48 | 0,75 | 11.3 | 4,69 | 341 | 8 | < 22 |
2022-05-10 | 9 | 1,54 | NP | 12.2 | NP | NP | NP | NP |
2022-06-07 | 9,7 | 1,75 | NP | 12.1 | NP | NP | NP | NP |
2022-07-05 | 9,4 | 1,69 | NP | 11.2 | NP | NP | NP | NP |
2022-08-02 | 9,7 | 1,55 | NP | 11,4 | NP | NP | NP | NP |
2022-08-30 | 9,4 | 1,61 | NP | 10.5 | NP | NP | NP | NP |
2022-09-27 | 9,6 | 1,62 | NP | 11,5 | NP | NP | NP | NP |
2022-10-25 | 9,3 | 1,51 | NP | 11.2 | NP | NP | NP | NP |
2022-11-27 | 9,3 | 1,49 | NP | 11.3 | NP | NP | NP | NP |
2022-12-21 | 8,9 | 1,44 | NP | 10.4 | NP | NP | NP | NP |
2023-01-18 | 9,1 | 1,42 | NP | 10.7 | NP | NP | NP | NP |
2023-01-30 | NP | 1,3 | NP | 11,5 | NP | NP | NP | NP |
2023-02-15 | 9 | 1,37 | NP | NP | NP | NP | NP | NP |
2023-03-15 | 9,5 | 1,41 | 2,44 | NP | 4,49 | 371 | < 7 | < 21 |
2023-04-12 | 9,4 | 1,52 | NP | NP | NP | NP | NP | NP |
2023-05-10 | 9 | 1,57 | NP | NP | NP | NP | NP | NP |
2023-06-30 | 9,4 | 2 | NP | 10,2 | NP | NP | NP | NP |
2023-08-02 | 8,9 | 1,9 | NP | NP | NP | NP | NP | NP |
2023-09-04 | 9,7 | 1,6 | NP | NP | NP | NP | NP | NP |
2023-10-02 | 8,9 | 1,4 | NP | NP | NP | NP | NP | NP |
2023-10-31 | 8,7 | 1,7 | NP | NP | NP | NP | NP | NP |
2023-11-30 | 8,4 | 1,6 | NP | NP | NP | NP | NP | NP |
2024-01-09 | 9 | 1,6 | 0,74 | NP | 5,61 | 376 | 24 | < 20 |
2024-02-06 | 9,1 | 1,6 | NP | NP | NP | NP | NP | NP |
2024-02-23 | 9,1 | 1,5 | 0,50 | NP | 4.3 | 434 | 31 | 10 |
2024-03-27 | 9,0 | 1,8 | NP | 12,9 | NP | NP | NP | NP |
Abbreviations Ca: calcemia; Crea: serum creatinine; CRP: C-Reactive Protein; β2M: serum β2-Microglobulina; Hb: hemoglobin; IgA, IgG, IgM: serum immunoglobulins; NP: Not Performed |
In any case, laboratory tests should always be correlated with clinical manifestations, imaging examinations, and bone marrow biopsy investigations.
In IgD MM, electrophoretic patterns showing the marked decrease of the γ-globulin zone and absence of monoclonal peaks have been widely documented [1, 8, 26].
In our case at diagnosis, theoretically, two peaks corresponding to the two MCs IgDλ and λ free should have been evident [15, 16]; instead, only a peak of 19.3 g/L, representative of sFLCλ (2510 mg/L, rFLC 0.0044), was detected on the electrophoresis trace, while the IgD paraprotein peak was undetectable due to its low serum levels [29]. Confirming this interpretation, the peak gradually decreased, until it disappeared, in proportion to the decrease in sFLCλ concentration, i.e., the increase in rFLC (Fig. 5). The latter parameter is compared with the results of immunofixations and serum electrophoresis in Table 1. The sIFE initially showed two IgDλ and λ free CMs, then only one λ free isotype MC was evident until the test resulted negative, while BJP λ disappeared in urine, in accordance with the response to the treatment plan.
Recent advances in diagnosis and treatment have improved outcomes in patients with IgD MM, although the clinical course is thought to be aggressive [3, 14]. Patients affected by IgD MM have a poor prognosis compared with other MM subtypes, with a median survival of 13 to 21 months [9].
Some studies suggest the use of bortezomib as a first-line drug because it effectively prolongs survival time [27], especially in younger patients [28]. Since patients with IgD MM have a shorter median survival compared to other subtypes [28, 29], according to some authors, the use of bortezomib could improve the prognosis especially in younger patients [30]. In a retrospective study [14] of 149 patients, an Overall Response Rate (ORR) was observed in 125 (83.9%), while 24 (15.4%) had progressive or stable disease, with median Overall Survival (mOS) ranging from 9 to 62 months. Novel Agents (NA = Bortezomib, Thalidomide and Lenalidomide) were administered to 111 (74.4%) patients, achieving a mOS of 23 months (range = 15-38.6). Conventional therapeutic agents like Melphalan, Vinblastine, Vincristine, Epirubicin and Ifosfamide were administered to 38 (25.5%) patients, resulting in an mOS of 14 months (range = 12.5–17). Data showed that bortezomib-based treatment protocols showed a higher Overall Response Rate (ORR = 94%, CR = 52%) than non-bortezomib-based treatment protocols (ORR = 77.8%, CR = 27.7%).
In our case, the patient underwent therapy according to VMP scheme (Bortezomib -Melphalan - Prednisone) obtaining a VGPR.
The introduction of anti-CD38 monoclonal antibody (mAb) in the treatment of MM also improved the outcome in IgD MM patients [14]. Daratumumab is a human IgG1κ mAb that at the recommended dosage (1800 mg/sc for 8 weeks, then every 2 weeks for 16 weeks, and then every 4 weeks thereafter) reaches peak serum concentrations and it is easily detectable in most SPE and sIFE. In our case, the diagnostic challenge was the question of whether the appearance of an IgGκ MC represented an isotypic switch or was an interference of the monoclonal drug administered. The answer to the diagnostic question was provided by the introduction of the new DIRA test, which allowed us to report with certainty that the monoclonal peak visible in SPE was caused by the administered drug.
Patients with Relapsed/Refractory Multiple Myeloma (RRMM) require treatments that induce a good depth and duration of response essential to achieve stabilization of quality of life. A recent review by Durer et al. [33] provided a set of recommendations for good clinical practice for RRMM patients that starts with careful consideration of disease-related (biochemical or clinical relapse, cytogenetic risk, aggressiveness) and host-related (age, performance status, comorbidities, frailty, bone marrow reserve, transplant eligibility, preferences, caregiver availability) factors in addition to treatment-related factors (type of drugs, number of prior lines, depth and duration of response, toxicity, and prior complications). The recommendations for good clinical practice reported by Durer follow the EMN (European Myeloma Network) recommendations for MM.