IgD multiple myeloma a descriptive report of 17 cases: survival and response to therapy

Immunoglobulin (Ig)D multiple myeloma (IgD MM) is a rare subtype of myeloma, accounts for less than 2% of all myelomas [1] and is accompanied with aggressive course, resistance to chemotherapy and poor outcome. It is often associated with relatively high frequencies of renal failure, extra osseous disease, hypercalcemia, amyloidosis and Bence-Jones proteinuria [2‐5]. The survival of patients with IgD MM has been reported to be shorter than that of patients with other types of M-protein [2, 4, 6]. However, there are reports of long survival in patients with IgD MM treated with alkylating drugs [7‐9], interferon-alfa monotherapy [10] or autologous stem cell transplantation (ASCT) [11‐15]. Over the past 10 years, there has been substantial progress in the treatment of MM, prospective randomized trials have shown the superiority of high-doses of chemotherapy with autologous stem cell transplantation (HDT/ASCT) over standard therapy (CT) and new drugs, such as immunomodulatory agents and proteasome inhibitors, have shown effectiveness against disease. These developments may have led to changes in the outcomes of IgD MM.

In this report we present the results of a retrospective analysis of 17 cases with IgD MM treated with CT or HDT/ASCT in six institutions of Multiple myeloma Latium-Region GIMEMA Working Group between 1993 and 2009.

A retrospective analysis was carried out of 17 patients with IgD MM diagnosed from 1993 to 2009 in six institutions from Multiple Myeloma Latium-Region GIMEMA Working Group. Patients who had overt MM based on International Myeloma Working Group (IMWG) diagnostic criteria were selected.

Six patients were treated with CT, five with Melphalan plus steroids based regimens and one with VAD (Vincristine, Adriamycin and Dexametasone) plus CED (Cyclophosphamide, Etoposide, Dexamethasone); one patient showed a CR, two VGPR, two PR and one SD. Thalidomide was used as maintenance in the patient who obtained CR after CT. The overall response rate (ORR) was 83%; after a median follow up of 38 months (range 19-60) for patient treated with conventional chemotherapy, the median OS was 34 months (95% CI 15- 54 months) and the median PFS was 18 months (95% CI 3-33 months). Median DOR was 7 months (95% CI 5-9 months).

Eleven patients underwent HDT/ASCT, as part of their front line therapy, five patients received single and six tandem ASCT. Six out of 11 patients received induction chemotherapy including thalidomide and/or bortezomib and five VAD. After ASCT single or tandem, five patients obtained CR, three VGPR, two PR and one SD. One patient in PR after HDT/ASCT received maintenance with bortezomib and another patient also in PR received Thalidomide as maintenance treatment both patients maintained PR. The ORR in patients treated with HDT/ASCT was 90% after a median follow up of 50 months (range 17-148); median OS, PFS [Figures 1, 2] and DOR are not reached. The log-rank test for DOR was P = 0.23.

The clinical features of our patients reported in this study underline the worse characteristics of IgD MM. As in other series described in the literature [18], we also found an advanced stage and a younger age at presentation, with more aggressive clinical course. In addition, the poor survival of the patients may be associated with problems related to delayed diagnosis [13, 19].

Patients with renal failure of unknown cause, bone pain, small serum M-protein bands, or unidentified Ig isotype should be suspected for IgD MM. However, the underlying tumor biology responsible for the differences between IgD MM and other MM isotypes remains to be defined.

IgD MM should be considered a rare subgroup of MM with aggressive features rather than a single parameter of poor prognosis.

Jancelewicz et al. [2] reported that λ light-chains are found in 90% and almost the totality of patients had Bence-Jones proteinuria. A mean survival of 13.7 months from diagnosis, that was worse than the common myelomas, was observed in this study. Bladé et al [4] reviews outcomes in 53 patients from 1965 to 1992 and observed λ light-chain disease in 60%, Bence Jones proteinuria in 96%, renal failure in 33% and hypercalcemia in 22%. Shimamoto et al [6] reviewed 165 cases with IgD MM and on multivariate analysis showed that λ light-chains and white blood cell count > 7 × 10⁹ where adverse prognostic markers. In our series we registered in 11 out of 17 patients (64%) the presence of λ light-chains and Bence-Jones proteinuria in 70%, renal impairment with eGFR < 50 ml/min in 8 cases (47%), extra osseous disease was not seen in our patients at diagnosis. Many studies have shown a poorer prognosis of IgD myeloma than other MM isotypes. Bladé et al. [4] observed an overall response to therapy of 58% with a median overall survival of 21 months and 5-years survival was 21%. However, these results were obtained before the use high-dose therapy. Wechalekar et al in 11 cases IgD myeloma treated with autologous stem cell transplantation reported 18% CR and 82% PR, compared with a group of 14 patients who received conventional chemotherapy alone in which was observed 0% CR and 43% PR. Maisnar et al [13] reviewed 26 cases with IgD MM; ten were treated with first-line high-dose chemotherapy using melphalan 200 mg/m² followed by ASCT and 70% achieved a CR and 100% had at least a PR. The median PFS was18 months for patients who received ASCT and 20 months for those who received conventional chemotherapy. However, the median OS for ASCT group had not been reached, in contrast the median OS for chemotherapy group was only 16 months, which was statistically significant (P = 0.005). More recently Kim et al [17] retrospectively reviewed 75 patients with IgD myeloma from the Korean Myeloma Registry data base; among 34 patients (45%) treated with ASCT who were in CR or PR, after induction therapy, had a median OS of 30 months (95% CI 17.7-42.3 months) significantly longer than that of patients treated with conventional chemotherapy (16.4 months, P = 0.012).

The small group of patients suffering from IgD multiple myeloma is rare and considered to have a poor prognosis compared to other MM isotypes. Our report, based on analysis of a cohort of 17 patients treated over two decades in six institutions, shows that the use of HDT/ASCT increased OS and PFS by 63% and 69%, respectively, in comparison with those of patients treated with conventional chemotherapy. Thus, the advantage of HDT/ASCT over conventional chemotherapy seems confirmed, although the small number of patients limited the statistical power of the analysis.

New drugs, such bortezomib, thalidomide, lenalidomide used as induction and consolidation in the stem cell transplantation program, may well improve the outcomes of IgDMM.

The clinical features and prognosis of patients with IgDMM differ from those that characterize patients with other immunoglobulin MM subtypes. The underlying tumor biology responsible for these differences remains to be determined. New treatment strategies that aim to induce high-quality responses before ASCT and maintain the response after ASCT may be needed to improve the outcomes of such patients.