The prognosis is highly variable between patients, from highly aggressive forms potentially lethal within a few weeks of diagnosis, to very indolent forms, with a disease course longer than 10-20 years. The Revised International Staging System (R-ISS) includes three stages of myeloma: I (best), II, and III (worst). With treatment, the 5 year survival rate is 82% in stage I, 62% in stage II, and 40% in stage III (as of 2015).

Prognosis depends on many factors, but the most important ones are the ISS stage  and DNA/biological  features such as  chromosomes: if chromosomes are normal, prognosis is relatively good, but 25% of myeloma patients have “high-risk” chromosomes in their plasma cells (e.g., the presence of 17p-, t4;14, or t14;16), and only about 30% of these patients are in remission at 2 years from diagnosis even with aggressive therapeutic approaches such as stem cell transplant. Of note, myeloma is characterized by clonal evolution, and therefore cases with normal cytogenetics at baseline may eventually transform and develop high-risk features over time.


Median Survival:
  About 6 months without treatment
  About 3-5 years with standard treatment (as of 2017)
  About 6-8 years with aggressive treatment that includes stem cell transplantation (as of 2017)
These are just statistical "medians", and they should be interpreted as such: outcomes of individual patients may be much worse or much better that those. In other words, myeloma patients have a very broad range of expected survival, and the above information is only a statistical "median" estimate, which means 50% of patients die before, 50% after, but obviously the individual patient may have a much worse or much better life expectancy than the average, depending not only on the therapy, but, most importantly, on the biologic behavior of the cancer. Obviously, patient-related factors, such as age and comorbidities, are important, but survival often does not depend on the patient nor on the doctor, but primarily on the type of myeloma, which could be indolent or aggressive. And this may even change over time, during the course of the disease, so that relatively indolent cases may not remain indolent, but they can transform into more aggressive ones. Ultimately, the prognosis of an individual patient is unknown, because each case is unique, and statistics apply only to populations of patients, not to single individuals.

It is important to note that results published by medical journal after clinical trials may appear better than those seen in routine clinical practice, with consecutive patients, because clinical trials select "better" patients, i.e., those with less comorbidities and good performance status. In fact, patients enrolled in clinical trials are typically younger, healthier, and more "motivated" than the average myeloma patient. Therefore, their clinical outcomes and survival published by clinical trials may not be representative of the whole myeloma patient population. This discrepancy may compromise the validity of the survival results published by reports of study protocols, as compared to those observed in the "real world".


Differences between unselected patients and participants in multiple myeloma clinical trials in US: a threat to external validity.
Leuk Lymphoma. 2016 Dec;57(12):2827-2832.
Costa LJ1, Hari PN2, Kumar SK3.

The role of initial clinical presentation, comorbidity and treatment in multiple myeloma patients on survival: a detailed population-based cohort study.
Eur J Clin Pharmacol. 2017 Jun;73(6):771-778.
Oortgiesen BE, van Roon EN, Joosten P, Kibbelaar RE, Storm H, Hovenga S, van Rees B, Woolthuis G, Veeger N, de Waal EG, Hoogendoorn M.
This is a population-based study of clinical outcomes in 225 patients who were diagnosed with symptomatic multiple myeloma in Friesland, a province of the Netherlands. This study is interesting even because it indicates that among patients (15) who decided not to receive any treatment, the median overall survival was only 3 months, as compared to 43 months in those who received treatment.


Common causes of death:
 - Infections (most common)
 - Renal failure
 - Refractory pancytopenia
 - Hyperviscosity syndrome


Most important prognostic factors:

1) Cytogenetic abnormalities
     - t(4;14)
     - t(14;16)
     - del(17p) - p53 deletion
     - 1q21 amplification
     - 1p deletion
At metaphase cytogenetics:
     - hypodiploidy (<45 chromosomes excluding -Y)
     - chromosome 13 abnormalities: partial deletion, complete deletion (monosomy), 13q translocations
The presence of chromosome 13 abnormalities is an important and independent adverse prognostic factor. Thus, karyotype analysis is an indispensable test for patients with MM. Patients with chromosome 13 abnormalities have a dismal prognosis, with OS of 12 months. Cytogenetic analysis identifies chromosome 13 abnormalities in 18% of newly diagnosed patients. These patients usually have the t(4;14) and 17p-, and monosomy 13 may be just a surrogate marker for these findings. Using interphase FISH, chromosome 13 abnormalities are detectable in 54% of patients.

2) Laboratory tests
     - Serum levels of beta2-microglobulin
     - LDH
     - CRP
     - IL-6 and serum-soluble IL-6 receptor (sIL-6R)
Beta2-microglobulin correlates with the myeloma cell mass and is one of the most powerful indicators of prognosis. According to some studies, it is more powerful than stage.

3) Plasma cell labeling index
The plasma cell labeling index (PCLI) is a measure of marrow plasma cells in the S phase of the cell cycle, and it estimates the proliferative capacity of the malignant plasma cells.
The prognosis is worse if patients have >1% cells in S phase in the BM.


Poor prognosis if:
 - t(4;14), 17p-, or 1q21 gain by FISH
 - Chromosome 13 abnormalities by metaphase cytogenetics
 - Multiple bone lesions
 - Renal failure (serum creatinine >2 mg/dL)
 - Short interval between asymptomatic illness and progressive disease
 - M-component >3.5 g/dL
 - Bence-Jones proteinuria
 - Elevated CRP, beta2-microglobulin, LDH
 - >5% circulating plasma cells



Expected average survival, with therapy:


 - According to the Durie-Salmon stage (1975):

    Stage IA...............61 months
    Stage IB, IIA, IIB.....55 months
    Stage IIIA.............30 months
    Stage IIIB.............15 months

- According to the ISS stage (2005):

    Stage I................62 months
    Stage II...............44 months
    Stage III..............29 months

- According to the Revised ISS stage (2015):

    Stage I................survival at 5-years 82%
    Stage II...............survival at 5-years 62%
    Stage III..............survival at 5-years 40%

R-ISS considers stage III as: ISS III + either hogh LDH or high-risk chromosomal abnormalities (17p-, t4;14, or t14;16).



Is the International Staging System superior to the Durie-Salmon staging system? A comparison in multiple myeloma patients undergoing autologous transplant.
Leukemia. 2009 Aug;23(8):1528-34.
Hari PN, Zhang MJ, Roy V, Pérez WS, Bashey A, To LB, Elfenbein G, Freytes CO, Gale RP, Gibson J, Kyle RA, Lazarus HM, McCarthy PL, Milone GA, Pavlovsky S, Reece DE, Schiller G, Vela-Ojeda J, Weisdorf D, Vesole D.
This study compared the DSS and ISS staging systems for predicting outcomes 729 myeloma patients treated with upfront ASCT (1995-2002). After a median follow-up of 56 months, the median overall survival was:
  - Stage I: 82 months by DSS and 64 months by ISS
  - Stage II: 68 months by DSS and 68 months by ISS
  - Stage III: 50 months by DSS and 45 months by ISS
The concordance between DSS and ISS was only 36%.




The International Myeloma Working Group (IMWG) proposed the use a combination of ISS and FISH for risk stratification in multiple myeloma, according to the following categories:

  - Low risk      (20%): age <55, ISS I/II, FISH without 17p13 del, t(4;14), 1q21 gain
                         Median overall survival >10 years
  - Standard risk (60%): all others
                         Median overall survival   7 years
  - High risk     (20%): ISS II/III, FISH with 17p13 del, t(4;14)
                         Median overall survival   2 years


IMWG consensus on risk stratification in multiple myeloma.
Leukemia. 2014 Feb;28(2):269-77.
Chng WJ, Dispenzieri A, Chim CS, Fonseca R, Goldschmidt H, Lentzsch S, Munshi N, Palumbo A, Miguel JS, Sonneveld P, Cavo M, Usmani S, Durie BG, Avet-Loiseau H.




Patients with pre-existing MGUS before the diagnosis of myeloma have a better prognosis after stem cell transplantation, presumably due to a more favorable biology and more indolent course of the disease compared with de novo myeloma.

Outcome after autologous stem cell transplantation for multiple myeloma in patients with preceding plasma cell disorders.
Br J Haematol. 2008 Apr;141(2):205-11.
Kumar SK, Dingli D, Lacy MQ, Dispenzieri A, Hayman SR, Buadi FK, Rajkumar SV, Litzow MR, Gertz MA.
Among 804 myeloma patients undergoing stem cell transplantation, 151 had a preexisting plasma cell disorder, such as MGUS, smoldering myeloma, or a solitary plasmacytoma. The two groups of patients had similar response rates to stem cell transplant. Patients with a prior diagnosis of MGUS had  a longer time to progression (27.5 vs 17.2 months, p= 0.01), and longer overall survival from transplant (80.2 vs 48.3 months, p= 0.03), whereas patients with a prior diagnosis of smoldering myeloma or solitary plasmacytoma had similar time to progression and overall survival to those of patients with de novo myeloma.

Impact of early relapse after auto-SCT for multiple myeloma.
Bone Marrow Transplant. 2008 Sep;42(6):413-20.
Kumar S, Mahmood ST, Lacy MQ, Dispenzieri A, Hayman SR, Buadi FK, Dingli D, Rajkumar SV, Litzow MR, Gertz MA.
Without maintenance therapy, nearly a fifth of myeloma patients relapse within a year of autologous stem cell transplant. In a study of 494 patients who underwent transplant within 12 months after the diagnosis of myeloma, early relapse (<12 months from transplant) was observed in 120 patients (24%). This group had a significantly shorter overall survival (median 26.6 months, vs 90.7 months for the rest of the patients, calculating survival from the time of diagnosis). Multivariate analysis found 3 factors predicting for early relapse:
  - Failure to achieve complete remission
  - >1 treatment regimen prior to transplant
  - Labeling index >1%
Patients who relapse within 12 months of an autologous transplant have a poor outcome.

Natural history of relapsed myeloma, refractory to immunomodulatory drugs and proteasome inhibitors: a multicenter IMWG study.
Leukemia. 2017 Nov;31(11):2443-2448.
Kumar SK, Dimopoulos MA, Kastritis E, Terpos E, Nahi H, Goldschmidt H, Hillengass J, Leleu X, Beksac M, Alsina M, Oriol A, Cavo M, Ocio EM, Mateos MV, O'Donnell EK, Vij R, Lokhorst HM, van de Donk NWCJ, Min C, Mark T, Turesson I, Hansson M, Ludwig H, Jagannath S, Delforge M, Kyriakou C, Hari P, Mellqvist U, Usmani SZ, Dytfeld D, Badros AZ, Moreau P, Kim K, Otero PR, Lee JH, Shustik C, Waller D, Chng WJ, Ozaki S, Lee JJ, de la Rubia J, Eom HS, Rosinol L, Lahuerta JJ, Sureda A, Kim JS, Durie BGM.
The authors of this study reviewed the clinical outcomes of 543 patients with multiple myeloma, when the disease became refractory to both an IMiD (lenalidomide or pomalidomide) and a proteasome inhibitor (bortezomib or carfilzomib). The median duration between the diagnosis of myeloma and the dual refractoriness was 3.1 years, and the median number of lines of therapy was 4 (range, 3-13). The median overall survival from the time of dual refractoriness was 13 months.

The presence of large focal lesions is a strong independent prognostic factor in multiple myeloma.
Blood. 2018 Jul 5;132(1):59-66.
Rasche L, Angtuaco EJ, Alpe TL, Gershner GH, McDonald JE, Samant RS, Kumar M, Van Hemert R, Epstein J, Deshpande S, Tytarenko R, Yaccoby S, Hillengass J, Thanendrarajan S, Schinke C, van Rhee F, Zangari M, Walker BA, Barlogie B, Morgan GJ, Davies FE, Weinhold N.
These authors analyzed data from 404 patients with newly diagnosed multiple myeloma who underwent skeletal MRI. They found that those patients with at least 3 large focal lesions (about 14% of cases) had worse prognosis, regardless of other factors, such as the R-ISS stage and gene expression profiling.  A focal lesion was defined as "large" when the product of the perpendicular diameter was greater than 5 cm2. Interestingly, even the number of focal lesions had a negative impact on prognosis, but it lost its negative prognostic impact after adjusting for the lesion size in the multivariate analysis.



The achievement of complete remission is associated with long-term outcome.

Complete remission sustained 3 years from treatment initiation is a powerful surrogate for extended survival in multiple myeloma.
Cancer. 2008 Jul 15;113(2):355-9.
Barlogie B, Anaissie E, Haessler J, van Rhee F, Pineda-Roman M, Hollmig K, Alsayed Y, Epstein J, Shaughnessy JD Jr, Crowley J.
Data from 3 clinical trials were reviewed, and sustained CR -for 3 years after the beginning of treatment- was found to be a superior surrogate for prolonged survival than the simple achievement of CR.

CR represents an early index of potential long survival in multiple myeloma.
Bone Marrow Transplant. 2010 Mar;45(3):498-504.
Wang M, Delasalle K, Feng L, Thomas S, Giralt S, Qazilbash M, Handy B, Lee JJ, Alexanian R.
A retrospective review of 758 myeloma patients showed that achievement of CR status was associated with long-term survival. Based on the disease status at 2 years from the beginning of the treatment, median survival was:
  - 2.7 years for patients with no response
  - 4.4 years for patients with partial response
  - 9.7 years for patients with complete response
Stem cell transplantation seemed more beneficial when done within 12 months from the diagnosis (395 patients), with a treatment-related mortality of 3%. Interestingly, no additional benefit was observed from stem cell transplantation if patients were already in CR after induction therapy. Median survival was:
  - 14.6 years in 29 patients in CR after induction therapy who received stem cell transplantation
  - 12.4 years in 23 patients in CR after induction therapy who did not receive stem cell transplantation
It seemed that the benefit of high-dose chemotherapy was due to its ability to convert patients in PR to CR. Achievement of CR was the most important prognostic factor for long-term survival, more relevant than stage and treatment modality. Only 9 patients remained in CR for >10 years, consistent with a very low cure fraction, estimated at 2%.

Complete response correlates with long-term progression-free and overall survival in elderly myeloma treated with novel agents: analysis of 1175 patients.
Blood. 2011 Mar 17;117(11):3025-31.
Gay F, Larocca A, Wijermans P, Cavallo F, Rossi D, Schaafsma R, Genuardi M, Romano A, Liberati AM, Siniscalchi A, Petrucci MT, Nozzoli C, Patriarca F, Offidani M, Ria R, Omedè P, Bruno B, Passera R, Musto P, Boccadoro M, Sonneveld P, Palumbo A.
This is a retrospective analysis of 1175 patients with newly diagnosed myeloma enrolled in multicenter clinical trials, after a median follow-up of 29 months.
  - PFS at 3 years: 67% in patients who achieved CR, and 27% in patients who achieved VGPR
  - OS at 3 years: 91% in patients who achieved CR, and 70% in patients who achieved VGPR



Prognostic impact of circulating plasma cells in patients with multiple myeloma: implications for plasma cell leukemia definition.
Haematologica. 2017 Jun;102(6):1099-1104.
Granell M, Calvo X, Garcia-Guiñón A, Escoda L, Abella E, Martínez CM, Teixidó M, Gimenez MT, Senín A, Sanz P, Campoy D, Vicent A, Arenillas L, Rosiñol L, Sierra J, Bladé J, de Larrea CF; GEMMAC (Grup per l’estudi del mieloma i l’amiloïdosi de Catalunya).
In this study, 482 patients with newly diagnosed myeloma were stratified into 4 groups, based on the review of the peripheral blood smear:
  - 0% circulating plasma cells (382 patients, 79%). Median survival was 47 months.
  - 1-4% circulating plasma cells (83 patients, 17%). Median survival was 50 months.
  - 5-20% circulating plasma cells (12 patients, 2.5%). Median survival was 6 months.
  - >20% circulating plasma cells (5 patients, 1%). This group represents those patients who are traditionally diagnosed with plasma cell leukemia. Median survival was 14 months.
 Of note, the prognosis of patients with 5-20% circulating plasma cells was similar to that of patients with plasma cell leukemia (i.e., >20%). Instead, the presence of 1-4% circulating plasma cells had no adverse impact on prognosis. 

Enumeration and characterization of circulating multiple myeloma cells in patients with plasma cell disorders.
Br J Haematol. 2018 Jan;180(1):71-81.
Foulk B, Schaffer M, Gross S, Rao C, Smirnov D, Connelly MC, Chaturvedi S, Reddy M, Brittingham G, Mata M, Repollet M, Rojas C, Auclair D, DeRome M; MMRF CoMMpass Network, Weiss B, Sasser AK.
The authors describe an automated assay to enumerate and characterize circulating myeloma cells, and tested it in over 1000 patient samples (including MGUS, smoldering myeloma, newly diagnosed symptomatic myeloma, and relapsed/refractory disease). The specimen consisted of 4 mL of peripheral blood, and numbers of circulating myeloma cells were considered high if >100/4 mL. Of note, results obtained by FISH correlated well with those seen in the bone marrow aspirates. There was a good correlation between number of circulating myeloma cells and multiple clinical parameters, for example ISS stage at baseline in newly diagnosed patients, response to therapy, remission, relapse, and survival. This assay represents not only a useful research tool, but it can be a non-invasive method to monitor the status and clinical behavior of plasma cell disorders.



Extramedullary vs medullary relapse after autologous or allogeneic hematopoietic stem cell transplantation (HSCT) in multiple myeloma (MM) and its correlation to clinical outcome.
Bone Marrow Transplant. 2004 Dec;34(12):1057-65.
Zeiser R, Deschler B, Bertz H, Finke J, Engelhardt M.
This study reviewed data of 78 myeloma patients treated with stem cell transplantation (autologous in 53 patients, and allogeneic in 25 patients), and it compared outcomes of 14 patients with "extramedullary relapse" vs 64 patients with "bone marrow relapse". The sites of extramedullary relapse were lungs, soft tissues, pericardium, skin, and CNS. OS and PFS survival in the group with extramedullary relapse were similar to those of the group with bone marrow relapse. Treatment with DLIs induced disease remission in 5 of 9 (56%) patients with bone marrow relapse, and in 3 of 4 (75%) patients with extramedullary relapse.

Soft-tissue extramedullary multiple myeloma prognosis is significantly worse in comparison to bone-related extramedullary relapse.
Haematologica. 2014 Feb;99(2):360-4.
Pour L, Sevcikova S, Greslikova H, Kupska R, Majkova P, Zahradova L, Sandecka V, Adam Z, Krejci M, Kuglik P, Hajek R.
Among 226 patients with relapsed myeloma, purely extramedullary disease was observed in 32 (14%). These patients had a poor prognosis, with median overall survival of 30 months from diagnosis.





Cell proliferation of myeloma plasma cells: comparison of the blood and marrow compartments.
Am J Hematol. 2004 Sep;77(1):7-11.
Kumar S, Rajkumar SV, Greipp PR, Witzig TE.
These authors compared the plasma cell labeling index (PCLI) of the bone marrow plasma cells with the PCLI of circulating plasma cells in 117 myeloma patients. The PCLI in the peripheral blood correlated with the PCLI in the bone marrow, and it was usually lower (median difference: 0.4), suggesting that myeloma cells find a more favorable microenvironment in the marrow. 27 of 117 patients had a PCLI higher in the peripheral blood than in the bone marrow, and these patients had a worse prognosis (median survival from the time of the test was 2 months, vs 12 months for the other 90 patients, p= 0.01).

Prognostic value of urinary pyridinium crosslinks and their derivatives in multiple myeloma.
Ann Hematol. 2005 Jan;84(1):19-24.
Samani KK, Brazier M, Mathiot C, Kamel S, Jamart J, Jaubert J, Blanc M, Azaïs I, Facon T, Leleu X.

Prognostic value of serum free light chain ratio at diagnosis in multiple myeloma.
Br J Haematol. 2007 May;137(3):240-3.
Kyrtsonis MC, Vassilakopoulos TP, Kafasi N, Sachanas S, Tzenou T, Papadogiannis A, Galanis Z, Kalpadakis C, Dimou M, Kyriakou E, Angelopoulou MK, Dimopoulou MN, Siakantaris MP, Dimitriadou EM, Kokoris SI, Panayiotidis P, Pangalis GA.
The serum free light chain ratio was obtained at baseline in 94 myeloma patients, and it was found to have prognostic value. Median FLC ratio at baseline was 3.6 in kappa-myeloma, and 45.1 in lambda-myeloma. A high level of FLC ratio, defined as a level higher than the median value for kappa-myeloma and lambda-myeloma, was associated with a worse outcome and it was an independent prognostic factor. The 5-year survival was 82% in patients with higher levels, and 30% in patients with lower levels.

High serum-free light chain levels and their rapid reduction in response to therapy define an aggressive multiple myeloma subtype with poor prognosis.
Blood. 2007 Aug 1;110(3):827-32.
van Rhee F, Bolejack V, Hollmig K, Pineda-Roman M, Anaissie E, Epstein J, Shaughnessy JD Jr, Zangari M, Tricot G, Mohiuddin A, Alsayed Y, Woods G, Crowley J, Barlogie B.
Serum FLC were measured at baseline and at several time points during induction therapy in myeloma 301 patients. FLC levels were >75 mg/dL were found at baseline in 33% of patients, and they had a negative prognostic impact. A rapid and deeper reduction of FLC seen during induction therapy was associated with aggressive disease and inferior outcome.

Prediction of survival using absolute lymphocyte count for newly diagnosed patients with multiple myeloma: a retrospective study.
Br J Haematol. 2008 Jun;141(6):792-8.
Ege H, Gertz MA, Markovic SN, Lacy MQ, Dispenzieri A, Hayman SR, Kumar SK, Porrata LF.
A retrospective analysis of the absolute lymphocyte count (ALC) was conducted in 537 patients with newly diagnosed multiple myeloma. ALC proved to be an important prognostic factor, even after multivariate analysis. After a median follow-up of 35.1 months, patients with ALC >1,400 had a superior overall survival compared with patients with ALC <1,400 (65 vs 26 months, p <0.01). The results suggested that the immune status plays an important role in the survival of MM.

Increased serum lactate dehydrongenase should be included among the variables that define very-high-risk multiple myeloma.
Clin Lymphoma Myeloma Leuk. 2011 Oct;11(5):409-13.
Gkotzamanidou M, Kastritis E, Gavriatopoulou MR, Nikitas N, Gika D, Mparmparousi D, Matsouka C, Terpos E, Dimopoulos MA.
High serum levels of lactate dehydrogenase (LDH) predict for inferior survival and add prognostic value to the ISS. Analyzed of 203 patients found that median overall survival was 54 months in patients with normal LDH, and 21 months in patients with increased LDH. Increased LDH identified subgroups of patients within the ISS II and III stages with worse outcome.

Polyclonal serum IgM level identifies a subgroup of multiple myeloma patients with low-risk clinicobiological features and superior survival.
Leuk Res. 2014 Jun;38(6):666-72.
An G, Wang H, Qin X, Shi L, Xu Y, Deng S, Sui W, Zhu G, Yao H, Yi S, Qin Y, Li F, Hao M, Ru K, Qi J, Cheng T, Wang J, Chang H, Qiu L.
This study of 485 myeloma patients found that the presence of normal IgM levels >50 mg/dL was associated with better biological features and better prognosis. Maybe this is due to the fact that higher IgM levels reflect a higher number of normal plasma cells/lower number of malignant plasma cells. 



Giampaolo Talamo, M.D.