Clinical studies in multiple myeloma

Multiple Myeloma (MM) is an incurably disease of the bone marrow. It is characterized by the uncontrolled growth of clonal plasma cells (PCs) and leads to production of non-functional gammaglobulin. Clinical features include loss of normal bone marrow function, defect bone structure and kidney failure.

The first historical cases were described as “mollities ossium” in the 1840s. Atypical urine samples were described already in the 1840s but the specific pattern on electrophoresis of serum from MM patients was described in 1939.

PCs are highly specialized cells derived from B-lymphocytes. Every single PC produces a single class of antibody - one heavy chain (IGH) of IgG, IgA, IgD or IgE class and one light chain (IgL) κ or λ.

Current evidence suggests MM evolves from a non-malignant state – MGUS, Monoclonal Gammopathy of Undetermined Significance.

Assessment of chromosomal abnormalities is powerful in predicting outcome and there are also data suggesting that different treatment modalities are more efficient in treating MM with certain abnormalities.

The first modern treatment attempts were performed in the 1940s with urethane. Combination therapy of melphalan and prednisone (MP) was invented in 1969 and remained standard therapy until early 2000s when Thalidomide and Bortezomib was introduced. Stem cell transplant as treatment for younger patients were evolved in the 1980s and is still standard therapy.

Paper I is based upon a retrospectively collected database of all 1837 MM patients diagnosed at 15 Swedish between the years 2000 to 2011. From this material, we selected all patients treated with melphalan and prednisone (MP) or MP with added thalidomide (MPT) in 1st 2nd 3rd and 4th lines of treatment, a total number of 888. A meta-analysis of six previous clinical studies comparing MP to MPT in previously untreated MM could show a 6 months benefit to MPT. In our study median OS from beginning of 1st line of treatment was 2.2/4.2 years after MP/MPT respectively, and in 2nd, 3rd and 4th line of treatment 1.8/2.9, 1.4/1.6 and 1.1/1.9 years (P < 0.0001, 0.003, 0.74 and 0.235). The benefit of MPT over MP was bigger in our study compared to the randomized clinical studies. Minor differences in patient characteristics could partly explain the difference, though the difference still remained after adjusting for these markers.

In paper II, we show, in a pan-Nordic collaborative study, with patients from Sweden, Norway and Denmark, the impact of chromosomal abnormality of gain 1q21. From a cohort of in total 930 patients, 347 patients, with known 1q21 status, were studied and divided into 3 groups; gain 1q21, other chromosomal abnormalities (del (13q), del (17p), t(4;14) and/or t(14;16)) (OA) and no chromosomal abnormalities (NA). We observed the most dismal outcome from the gain 1q21 group and best outcome in NA with OA in between, treating with conventional cytostatic drugs. Adding Thal, Bor or Len to treatment could overcome poor prognosis in the NA group, but not for patients with gain 1q21.

Paper III and IV were both based on a prospective clinical study on Lenalidomide (Len) naïve relapsed or refractory MM patients, starting at the second line of treatment, in two parts, studying Len in combination with Dexamethasone (Dex). The first part, an observational study on LenDex in standard dosing up to 9 cycles with 133 participating patients showed a good response rate (79% ≥PR) and a median time to progression (TTP) of 19 months. At response, PR or better, and two more consolidating cycles, patients were offered to enter a randomized phase II study, randomizing between continuous LenDex treatment and Len as single drug. There was a statistically insignificant trend to better progression free survival (PFS) in the LenDex group. No difference in overall survival (OS) could be shown.

In the fourth study we looked upon whether different single nucleotide polymorphisms (SNPs) in the ATP-binding cassette sub-family B member ABCB1 gene, encoding P-glycoprotein (P-gp) could have clinically effect on response rate and survival in the same patient cohort. P-glycoprotein is a transmembrane transport protein that is responsible for the extrusion of several drugs over the cell membrane. It is localized, among others, in the intestinal mucosa and the kidney tubules and this protein could both affect uptake and excretion of several drugs. ABCB1 is known as a marker for resistance to different chemotherapeutic agents. In our study we could show no significant differs in response or survival data between groups with different SNPs in the ABCB1 gene in the whole population, but in the low risk group according to cytogenetics, there was a significant difference in time to progression from difference in SNP in 1199G>A genotype, favoring patients with G/A over G/G genotype.

List of scientific papers

I. Addition of thalidomide to melphalan and prednisone treatment prolongs survival in multiple myeloma : a retrospective population based study of 1162 patients. JOHAN LUND, Katarina Uttervall, Johan Liwing, Gösta Gahrton, Evren Alici, Johan Aschan, Erik Holmberg, Hareth Nahi. European Journal of Haematology, 2014, 92(1), 19-25
https://doi.org/10.1111/ejh.12213

II. Proteasome inhibitors and IMiDs can overcome some high-risk cytogenetics in multiple myeloma but not gain 1q21. Hareth Nahi, Thea Kristin Våtsveen, JOHAN LUND, Bart M.S. Heeg, Birgitte Preiss, Evren Alici, Michael Boe Møller, Karin Fahl Wader, Hanne E.H. Møller, Lill Anny Grøseth, Brian Østergaard, Hong Yan Dai, Erik Holmberg, Gösta Gahrton, Anders Waage, Niels Abildgaard. European Journal of Haematology, 2016, 96(1), 46-54
https://doi.org/10.1111/ejh.12546

III. Lenalidomide vs. lenalidomide/dexamethasone maintenance after second-line lenalidomide/dexamethasone induction in Multiple Myeloma. JOHAN LUND, Astrid Gruber, Birgitta Lauri, Sigrid Karstorp, Adil Duru, Cecilie Blimark, Agneta Swedin, Markus Hansson, Karin Forsberg, Lucia Ahlberg, Conny Carlsson, Anders Waage, Peter Gimsing, Annette Juul Vangsted, Ulf Frølund, Erik Holmberg, Evren Alici, Mats Hardling, Ulf-Henrik Mellqvist, Hareth Nahi. [Manuscript]

IV. Pharmacogenetic study of the impact of ABCB1 Single nucleotide polymorphisms on the outcome in lenalidomide treated multiple myeloma patients – results from a Phase IV and a Phase II randomized study. Ingrid Jakobsen Falk, JOHAN LUND, Henrik Gréen, Astrid Gruber, Evren Alici, Birgitta Lauri, Cecilie Blimark, Ulf-Henrik Mellqvist, Agneta Swedin, Karin Forsberg, Conny Carlsson, Mats Hardling, Lucia Ahlberg, Kourosh Lofti, Hareth Nahi. [Manuscript]